Cirrhosis, Liver
Conditions
Keywords
Hepatitis C liver fibrosis
Brief summary
The purpose of this study is to examine the safety and effectiveness of GI262570 compared to placebo (a pill that looks exactly like GI262570 but contains no active medicine) in improving specific tests that indicate the degree of liver fibrosis (scarring). Subjects who are enrolled in the study must have had prior treatment with interferon (either pegylated or standard interferon) plus ribavirin for at least 12 weeks to treat their hepatitis C, but either failed to clear the virus or didn't tolerate the treatment.
Interventions
DRUGGI262570 0.5 mg
GI262570 0.5 mg
DRUGGI262570 1.0 mg
GI262570 1.0 mg
DRUGPlacebo
Placebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
40 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* A subject will be eligible for inclusion in this study only if all of the following criteria apply: * Age between 40 and 70 years, inclusive. * Documented positive serology for HCV antibody by a second generation or higher assay. * Serum HCV RNA positive and HCV viral Genotype 1 at pre-screening visit. * Ishak fibrosis score of 2, 3 or 4. * Failure to achieve sustained virologic response (SVR) with previous interferon (standard or pegylated) and ribavirin treatment administered at a minimum dose of 3mU three times weekly or equivalent, for at least 12 weeks. Reasons for failure may include failure to respond to treatment or intolerability to optimal treatment. Prior treatment with interferon/ribavirin must have been discontinued at least 11 months prior to the biopsy date. * Male or female; a female is eligible to enter and participate in this study if she is of: 1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or, 2. child-bearing potential, has a negative serum pregnancy test at screen, and agrees to one of the following: * Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the investigational drug, (a minimum of 5 half-lives or longer if the pharmacodynamic profile of the investigational drug warrants a longer time period); or, * Female sterilization; or, * Has a male partner who is sterilized; or, * Implants of levonorgestrel; or, * Injectable progestogen; or, * Oral contraceptive (combined or progestogen only) , must be stable for 3 months prior to study entry; or, * Any intrauterine device (IUD) with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criterion); or, * Any other methods with published data showing that the lowest expected failure rate for that method is less than 1% per year; or, * Barrier method only if used in combination with any of the above acceptable methods. * Availability and willingness of subject to provide written informed consent.
Exclusion criteria
A subject will not be eligible for inclusion in this study if any of the following criteria apply: * History of ascites, variceal hemorrhage, hepatic encephalopathy, spontaneous bacterial peritonitis or other signs of hepatic decompensation. * Current or historical evidence suggestive of ischemic heart disease or other cardiovascular disease that in the investigator's opinion may adversely impact the safety of the subject during the conduct of the study. Evidence suggestive of cardiovascular disease may come from a number of sources, including clinical history, physical exam, electrocardiogram, laboratory testing, and radiographic procedures. * New York Heart Association (NYHA) Functional Class 1, 2, 3, or 4 cardiac status * Co-infection with HBV or HIV. * Liver histology consistent with any other co-existing cause of chronic liver disease. * Documented evidence of a hepatic mass lesion suspicious for hepatocellular carcinoma. * Alpha-fetoprotein \> 200ng/mL at pre-screening. * Inadequate hematologic function defined by any of the following: Hemoglobin (\<12.5 g/dL for men)(\<12.0 g/dL for women) Absolute Neutrophil Count (ANC) (\<1.0 x 10\^9/L) Platelets (\<130X/10\^9/L) * Inadequate renal function defined as: Serum creatinine (\>1.5mg/dL (≥130mmol/L)) Calculated creatinine clearance as calculated by Cockcroft and Gault (\<60mL/min) * Serum ALT level ≥5 x ULN. * Albumin \<3.2g/dL. * Total bilirubin \>1.2 x ULN. * Prothrombin time \> 15 seconds or International normalized ratio (INR) \> 1.3. * Organ, stem cell, or bone marrow transplant. * Serious concurrent medical illness that in the investigator's opinion might interfere with therapy. This includes significant systemic illnesses (other than liver disease) such as chronic pancreatitis. * Active systemic autoimmune disorder. * A pre-existing condition interfering with normal gastrointestinal anatomy or motility, and/or renal function that could interfere with the absorption, metabolism, and/or excretion of the study drugs. * Other medical conditions that, in the investigator's opinion, might interfere with compliance with therapy, participation in the study or interpretation of results. * Pregnancy (or lactation) or, in subjects capable of bearing children, inability/unwillingness to practice adequate contraception. * Females of child-bearing potential (post-puberty) unwilling or unable to have pregnancy testing at any study visit. * Therapy with systemic cytotoxic agents, immunomodulators, or immunosuppressive therapy requiring use of more than 5mg of prednisone (or its equivalent) per day. * Therapy with a systemic antiviral agent (with the exception of prophylaxis or treatment of influenza or chronic HSV) within the past 30 days. * Concurrent participation in another clinical trial in which the subject is or will be exposed to another investigational or a non-investigational drug or device within 30 days of the screening visit. * Current therapy or anticipated need for therapy with hypoglycemic drugs (e.g., insulin, sulfonylurea or metformin). * Known hypersensitivity to GI262570, or to any component of the GI262570 soft gelatin capsules, dispersion tablets or the sodium salt tablet or to PPARg agonists. * A history of hepatotoxicity to TZDs and/or a history of severe edema or medically serious fluid-related events associated with the use of TZDs. * Use of other PPAR agonists (e.g., rosiglitazone, pioglitazone) within 1 year from the start of dosing. * Active alcohol abuse within the past 1 year. * Use of illegal drugs in the past 1 year. 30a. Macular edema or history of macular edema.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52 | Baseline and Week 52 | A percutaneous liver biopsy was obtained at the screening visit and at Week 52. A new liver biopsy at the screening visit was not taken in the event that a previous liver biopsy taken within 120 days of the Baseline /Day 1 visit (day of first dose), and the tissue block was available. The immunohistochemical marker assessed was smooth muscle alpha-actin (aSMA). Sections of the liver biopsies were stained by standard immunocytochemical techniques using a monoclonal antibody to smooth muscle actin with 'very intense purple' as the detection chromogen. This gives a reddish-purple color to the activated stellate cells, which strongly contrasts with the rest of the tissue. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. The values are presented as proportion of positive area over total area. |
| Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis | Baseline and at Week 52 | A percutaneous liver biopsy was obtained at the screening visit and at Week 52. A new liver biopsy at the screening visit was not taken in the event that a previous liver biopsy taken within 120 days of the Baseline /Day 1 visit (day of first dose), and the tissue block was available. Morphometric analysis was performed using specimens stained with Sirius red and computerized image analysis. Sirius red was used to stain extracellular collagen in liver sections. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. The values are presented as proportion of positive area over total area. |
| Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Week 52 | In ranked assessment (fibrosis and necroinflammation), available slides from each participant were evaluated as to whether one slide presents a globally more benign histopathology or whether the matched slides comprise globally equivalent histologic patterns. Subsequent data analysis revealed whether slides scored (within matched pairs of slides) as more benign occurred in different proportions of the Week 52 liver biopsies, according to treatment group. The number of participants with paired biopsies was based on the number with a Rank Assessment. |
| Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to 4 weeks post treatment (52 weeks) | AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. |
| Number of Participants With Abnormal ECG Findings | Up to 4 weeks post-treatment (52 weeks) | A standardized 12-lead ECGs were recorded at pre-screening, and pre-dose, at Baseline/Day 1, Weeks 16, 34, and 52 or withdrawal and at the 4 week follow-up visit. Any conditions such as bundle branch block, repolarization, depolarization, abnormal sinus rhythms, atrial fibrillation etc. are considered to be clinically abnormal findings. |
| Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Up to 4 weeks post-treatment (52 weeks) | Clinical laboratory parameters: Alkaline phosphatase, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Total bilirubin, Cholesterol, Carbon dioxide content/Bicarbonate (CO2/HCO3), Creatinine, Glucose, Hemoglobin, Potassium, Low density lipid (LDL) cholesterol, Lymphocytes, Sodium, Segmented neutrophils, Platelet count, White blood cell (WBC) count were assessed for change in grade toxicities. Toxicities were graded as grade 1 to grade 4 in increasing order of severity of toxicity. Thus grade 4 indicating severe toxicity. Only those parameters with grade 3 and 4 toxicities are presented. |
| Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | Baseline and up to 4 weeks post-treatment (52 weeks) | SBP and DBP readings were taken at pre-screening, pre-dose after 10 minutes of rest, at Baseline/Day 1, weeks 2, 4, 10, 16, 22, 28, 34, 40, 46, and 52 or WD and at the 4 week follow-up visit. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
| Mean Change From Baseline in Heart Rate | Baseline and up to 4 weeks post-treatment (52 weeks) | Heart rate assessment were done at pre-screening, pre-dose after 10 minutes of rest, at Baseline/Day 1, weeks 2, 4, 10, 16, 22, 28, 34, 40, 46, and 52 or WD and at the 4 week follow-up visit. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to be missing. |
| Number of Participants With Fluid Retention Events | Up to 4 weeks post-treatment (52 weeks) | Fluid retention event was one of the AEs reported. AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Change From Baseline in Serum ALT Over Time | Baseline and up to 4 weeks post-treatment (52 weeks) | ALT was assessed as per upper limit of normal where the normal range was 0-48 international units per liter. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
| Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52 | Baseline and Week 52 | Value at Day 1 visit (day of first dose) was considered as Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
| Median Change From Baseline in Serum HCV RNA Levels Over Time | Baseline and up to 4 weeks post-treatment (52 weeks) | Serum for HCV RNA levels were collected at pre-screen, Baseline, Week 28, Week 52, and at the 4 week follow up visit. Value at Day 1 visit (day of first dose) was considered as Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
| Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2 | At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2 | At 0 (pre-morning dose )1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Sample s for Week 2 serial group were collected at 0 (pre-morning dose )1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | Week 52 | Progression was defined as an increase by at least one point in the fibrosis score. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score. |
| Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| DN Cmax of GI262570 on Week 2 | At 0 (pre-morning dose) 1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Samples for Week 2 serial group were collected at 0 (pre-morning dose) 1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| GI262570 Serum Concentrations on Week 2, 16, 28, 40, and Week 52 | Weeks 2, 16, 28, 40 and 52 | Samples for Week 2 serial group were planned to be collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. For Weeks 16 and 40 samples were planned to be collected at 0 (pre-morning dose)1 and between 1.5-6 hour post-morning dose 2. For Weeks 28 and 52 samples were planned to be collected at 0 (pre-morning dose)1 and between 6-10 hour post-morning dose 2. |
| Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2 | At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | Week 52 | Regression was defined as a decrease by at least one point in the fibrosis score. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score. |
| Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52 | Week 52 | No change was defined as having the same score at both Baseline and at Week 52. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score. |
| Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Screening and Week 52 | Ishak score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The necroinflammatory score is the combined score for necrosis and inflammation domains and ranged from 0 (best) to 14 (worst). Change from screening was calculated as the post screening assessment minus the screening assessment for a given parameter. |
| Mean Change From Screening in Metavir Scores at Week 52 | Screening and Week 52 | Metavir activity score ranged from 0 to 3 (higher score indicates severe symptoms of necrosis). 0: Piecemeal necrosis (PMN) absent and lobular necrosis (LN) absent or slight, 1: PMN slight and LN moderate, 2: PMN moderate and LN severe, 3: PMN severe. Metavir fibrosis score ranged from 0 to 4 (higher score indicates severe symptoms of necrosis). 0: No fibrosis, 1: Portal fibrosis without septa, 2: Portal fibrosis with septa, 3: Septal fibrosis without cirrhosis, 4: Cirrhosis. Change from screening was calculated as the post screening assessment minus the screening assessment for a given parameter. |
| Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | Baseline and Week 52 | FibroTest was for the assessment of fibrosis. Fibro test was calculated using an original combination of five highly concentrated serum biochemical markers; alpha-2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin and gammaglutamyltransferase. FibroTest scores range from 0.00 to 1.00 where 0.0-0.21 is no fibrosis and \>= 0.59 is cirrhosis. Acti-test was calculated using 6 serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT and alanine aminotransferase. ActiTest was used for the assessment of necroinflammatory activity. Test score ranges from 0.00 to 1.00, where 0.00-0.17 indicates no necrosis and \>= 0.61 indicates severe necrosis. Day 1 value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
| Mean Change From Baseline in Serum ALT Levels | Baseline and Week 52 | ALT was assessed as per upper limit of normal where the normal range was 0-48 international units per liter. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
| Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570 | At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2 | Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily. |
| Mean Change From Baseline in Measures of Insulin Resistance | Baseline and Week 52 | Insulin resistance was measured using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Belfiore Insulin Sensitivity Index (ISI) and Quantitative Insulin Sensitivity Check Index (QUICKI). HOMA-IR = fasting plasma insulin\*fasting plasma glucose / 22.5 and ISI = 2 / \[(fasting plasma glucose from the participant / fasting plasma glucose normal reference range)\*( fasting plasma insulin from the participant / fasting plasma insulin normal reference range) + 1\] and QUICKI = 1/(log\[fasting plasma Insulin\] + log\[fasting plasma glucose\]). Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. |
Countries
Australia, Canada, Czechia, Germany, Israel, Malaysia, New Zealand, Puerto Rico, Romania, Russia, Singapore, South Korea, Taiwan, United States
Participant flow
Recruitment details
The study was conducted in North America, Europe, and the International region. There were 22 study sites in Europe, 9 study sites in the International region and 45 study sites in North America. The study was conducted duration 02-November-2005 to 03-March-2008.
Pre-assignment details
The study consisted of a pre-screening visit (within 60 days of first dose) and a screen visit. For this study, 110 sites screened 863 participants. Of these participants, 265 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52. | 88 |
| GI262570 0.5 mg Participants received GI262570 0.5 mg. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52. | 89 |
| GI262570 1.0 mg Participants received GI262570 1.0 mg once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52. | 88 |
| Total | 265 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 7 | 5 |
| Overall Study | Elevated liver enzymes | 1 | 0 | 0 |
| Overall Study | Lack of compliance with protocol | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Participant randomized by mistake | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 1 |
| Overall Study | Safety reasons | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo | GI262570 0.5 mg | GI262570 1.0 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 52.1 Years STANDARD_DEVIATION 5.64 | 52.2 Years STANDARD_DEVIATION 7.25 | 51.4 Years STANDARD_DEVIATION 5.81 | 51.9 Years STANDARD_DEVIATION 6.27 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 6 Participants | 7 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 14 Participants | 9 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 63 Participants | 67 Participants | 68 Participants | 198 Participants |
| Sex: Female, Male Female | 35 Participants | 36 Participants | 29 Participants | 100 Participants |
| Sex: Female, Male Male | 53 Participants | 53 Participants | 59 Participants | 165 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 88 | 0 / 89 | 0 / 88 |
| other Total, other adverse events | 58 / 88 | 50 / 89 | 55 / 88 |
| serious Total, serious adverse events | 7 / 88 | 10 / 89 | 6 / 88 |
Outcome results
Primary
Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis
A percutaneous liver biopsy was obtained at the screening visit and at Week 52. A new liver biopsy at the screening visit was not taken in the event that a previous liver biopsy taken within 120 days of the Baseline /Day 1 visit (day of first dose), and the tissue block was available. Morphometric analysis was performed using specimens stained with Sirius red and computerized image analysis. Sirius red was used to stain extracellular collagen in liver sections. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. The values are presented as proportion of positive area over total area.
Time frame: Baseline and at Week 52
Population: MITT Population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis | 0.02541 Ratio of positive area | Standard Deviation 0.058338 |
| GI262570 0.5mg | Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis | 0.02613 Ratio of positive area | Standard Deviation 0.055985 |
| GI262570 1.0mg | Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis | 0.02527 Ratio of positive area | Standard Deviation 0.060665 |
p-value: 0.9157reduced regression model
p-value: 0.9501reduced regression model
Primary
Mean Change From Baseline in Heart Rate
Heart rate assessment were done at pre-screening, pre-dose after 10 minutes of rest, at Baseline/Day 1, weeks 2, 4, 10, 16, 22, 28, 34, 40, 46, and 52 or WD and at the 4 week follow-up visit. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to be missing.
Time frame: Baseline and up to 4 weeks post-treatment (52 weeks)
Population: As treated population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in Heart Rate | Week 4 | 0.35 beats per minute | Standard Deviation 9.726 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 46 | 1.18 beats per minute | Standard Deviation 9.411 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 22 | 2.23 beats per minute | Standard Deviation 9.12 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 2 | 1.08 beats per minute | Standard Deviation 8.763 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 40 | -0.11 beats per minute | Standard Deviation 8.34 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 28 | 0.80 beats per minute | Standard Deviation 8.857 |
| Placebo | Mean Change From Baseline in Heart Rate | Withdrawal | 5.27 beats per minute | Standard Deviation 14.107 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 34 | 0.89 beats per minute | Standard Deviation 9.983 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 10 | 2.04 beats per minute | Standard Deviation 8.824 |
| Placebo | Mean Change From Baseline in Heart Rate | Post-treatment | 1.20 beats per minute | Standard Deviation 10.184 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 52 | 1.04 beats per minute | Standard Deviation 9.3 |
| Placebo | Mean Change From Baseline in Heart Rate | Week 16 | -0.44 beats per minute | Standard Deviation 8.425 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Post-treatment | -0.42 beats per minute | Standard Deviation 10.287 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 46 | -1.01 beats per minute | Standard Deviation 10.36 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 2 | -1.92 beats per minute | Standard Deviation 7.143 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 4 | 0.55 beats per minute | Standard Deviation 10.223 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 10 | 0.49 beats per minute | Standard Deviation 8.771 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 16 | -0.33 beats per minute | Standard Deviation 9.295 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 22 | -0.10 beats per minute | Standard Deviation 10.706 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 28 | -1.54 beats per minute | Standard Deviation 8.53 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 34 | 0.77 beats per minute | Standard Deviation 9.485 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 40 | -1.89 beats per minute | Standard Deviation 9.169 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Week 52 | -0.26 beats per minute | Standard Deviation 9.656 |
| GI262570 0.5mg | Mean Change From Baseline in Heart Rate | Withdrawal | 1.00 beats per minute | Standard Deviation 12.062 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Withdrawal | -1.17 beats per minute | Standard Deviation 3.061 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 40 | 0.09 beats per minute | Standard Deviation 11.101 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 16 | 0.55 beats per minute | Standard Deviation 11.07 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 46 | 1.08 beats per minute | Standard Deviation 12.056 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 10 | 0.83 beats per minute | Standard Deviation 8.747 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 2 | -0.28 beats per minute | Standard Deviation 8.554 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 52 | -2.09 beats per minute | Standard Deviation 12.197 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 4 | 1.80 beats per minute | Standard Deviation 10.221 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 28 | 0.05 beats per minute | Standard Deviation 8.237 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Post-treatment | 0.15 beats per minute | Standard Deviation 11.34 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 34 | -0.13 beats per minute | Standard Deviation 10.655 |
| GI262570 1.0mg | Mean Change From Baseline in Heart Rate | Week 22 | 3.23 beats per minute | Standard Deviation 12.141 |
Primary
Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52
A percutaneous liver biopsy was obtained at the screening visit and at Week 52. A new liver biopsy at the screening visit was not taken in the event that a previous liver biopsy taken within 120 days of the Baseline /Day 1 visit (day of first dose), and the tissue block was available. The immunohistochemical marker assessed was smooth muscle alpha-actin (aSMA). Sections of the liver biopsies were stained by standard immunocytochemical techniques using a monoclonal antibody to smooth muscle actin with 'very intense purple' as the detection chromogen. This gives a reddish-purple color to the activated stellate cells, which strongly contrasts with the rest of the tissue. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. The values are presented as proportion of positive area over total area.
Time frame: Baseline and Week 52
Population: Modified Intent to Treat (MITT) Population consisted of all participants with chronic hepatitis C randomized, regardless of whether or not the study drug was actually taken or if the participant completed the planned duration of the study. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52 | 0.02065 Ratio of positive area | Standard Deviation 0.04762 |
| GI262570 0.5mg | Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52 | 0.02819 Ratio of positive area | Standard Deviation 0.04816 |
| GI262570 1.0mg | Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52 | 0.02914 Ratio of positive area | Standard Deviation 0.040948 |
p-value: 0.3608reduced regression model
p-value: 0.3575reduced regression model
Primary
Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP)
SBP and DBP readings were taken at pre-screening, pre-dose after 10 minutes of rest, at Baseline/Day 1, weeks 2, 4, 10, 16, 22, 28, 34, 40, 46, and 52 or WD and at the 4 week follow-up visit. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and up to 4 weeks post-treatment (52 weeks)
Population: As Treated Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 34 | 0.40 Millimeter of mercury | Standard Deviation 11.48 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 4 | 1.12 Millimeter of mercury | Standard Deviation 8.793 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 10 | 0.94 Millimeter of mercury | Standard Deviation 9.195 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 16 | 0.31 Millimeter of mercury | Standard Deviation 9.194 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 22 | 1.18 Millimeter of mercury | Standard Deviation 10.264 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 28 | 0.87 Millimeter of mercury | Standard Deviation 10.529 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 2 | -0.06 Millimeter of mercury | Standard Deviation 12.347 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 40 | 0.05 Millimeter of mercury | Standard Deviation 10.136 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 46 | 0.95 Millimeter of mercury | Standard Deviation 10.62 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 52 | -0.01 Millimeter of mercury | Standard Deviation 10.177 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Withdrawal | 2.45 Millimeter of mercury | Standard Deviation 9.015 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, post-treatment | 0.66 Millimeter of mercury | Standard Deviation 11.085 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 2 | 0.17 Millimeter of mercury | Standard Deviation 16.7 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 4 | 0.78 Millimeter of mercury | Standard Deviation 16.821 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 10 | 2.95 Millimeter of mercury | Standard Deviation 16.888 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 16 | 0.83 Millimeter of mercury | Standard Deviation 15.621 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 22 | 0.45 Millimeter of mercury | Standard Deviation 18.161 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 28 | -1.82 Millimeter of mercury | Standard Deviation 20.285 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 34 | 0.95 Millimeter of mercury | Standard Deviation 19.558 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 40 | -1.34 Millimeter of mercury | Standard Deviation 19.616 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 46 | -0.53 Millimeter of mercury | Standard Deviation 15.173 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 52 | 0.15 Millimeter of mercury | Standard Deviation 18.95 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Withdrawal | 5.09 Millimeter of mercury | Standard Deviation 25.126 |
| Placebo | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Post-treatment | 0.25 Millimeter of mercury | Standard Deviation 21.747 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 52 | 1.92 Millimeter of mercury | Standard Deviation 13.352 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 2 | 0.60 Millimeter of mercury | Standard Deviation 9.129 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 2 | -0.53 Millimeter of mercury | Standard Deviation 14.095 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 22 | -1.79 Millimeter of mercury | Standard Deviation 14.361 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 4 | -1.31 Millimeter of mercury | Standard Deviation 7.56 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Withdrawal | 0.89 Millimeter of mercury | Standard Deviation 8.852 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 46 | -1.85 Millimeter of mercury | Standard Deviation 12.158 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 10 | -1.62 Millimeter of mercury | Standard Deviation 10.032 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 4 | -1.34 Millimeter of mercury | Standard Deviation 13.333 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Withdrawal | -0.44 Millimeter of mercury | Standard Deviation 21.83 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 16 | -2.00 Millimeter of mercury | Standard Deviation 9.664 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 52 | -0.64 Millimeter of mercury | Standard Deviation 9.807 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 28 | -2.16 Millimeter of mercury | Standard Deviation 15.26 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 22 | -2.46 Millimeter of mercury | Standard Deviation 9.648 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 10 | -0.47 Millimeter of mercury | Standard Deviation 14.524 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, post-treatment | -0.29 Millimeter of mercury | Standard Deviation 10.86 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 28 | -1.09 Millimeter of mercury | Standard Deviation 9.664 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 46 | -1.16 Millimeter of mercury | Standard Deviation 9.203 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Post-treatment | 1.69 Millimeter of mercury | Standard Deviation 13.431 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 34 | -1.38 Millimeter of mercury | Standard Deviation 9.242 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 16 | -1.79 Millimeter of mercury | Standard Deviation 15.496 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 34 | -1.86 Millimeter of mercury | Standard Deviation 15.059 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 40 | -2.20 Millimeter of mercury | Standard Deviation 8.947 |
| GI262570 0.5mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 40 | -1.04 Millimeter of mercury | Standard Deviation 13.085 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 40 | 1.16 Millimeter of mercury | Standard Deviation 9.302 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 46 | 1.29 Millimeter of mercury | Standard Deviation 8.423 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 52 | -0.13 Millimeter of mercury | Standard Deviation 6.855 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Withdrawal | 1.00 Millimeter of mercury | Standard Deviation 5.933 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 40 | -1.23 Millimeter of mercury | Standard Deviation 14.371 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, post-treatment | 0.49 Millimeter of mercury | Standard Deviation 9.634 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Withdrawal | -0.17 Millimeter of mercury | Standard Deviation 3.488 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 2 | 0.49 Millimeter of mercury | Standard Deviation 12.516 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 4 | -0.80 Millimeter of mercury | Standard Deviation 12.343 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 46 | 0.30 Millimeter of mercury | Standard Deviation 13.67 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 10 | -0.85 Millimeter of mercury | Standard Deviation 13.293 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Post-treatment | 3.52 Millimeter of mercury | Standard Deviation 16.931 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 16 | 0.10 Millimeter of mercury | Standard Deviation 11.008 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 2 | 0.17 Millimeter of mercury | Standard Deviation 8.171 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 4 | -0.02 Millimeter of mercury | Standard Deviation 8.018 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 22 | 0.59 Millimeter of mercury | Standard Deviation 12.217 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 10 | 0.00 Millimeter of mercury | Standard Deviation 7.309 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 52 | -0.21 Millimeter of mercury | Standard Deviation 12.414 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 16 | 0.06 Millimeter of mercury | Standard Deviation 8.226 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 22 | 0.93 Millimeter of mercury | Standard Deviation 8.194 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 28 | 1.69 Millimeter of mercury | Standard Deviation 14.782 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 28 | 0.15 Millimeter of mercury | Standard Deviation 9.231 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | DBP, Week 34 | 0.70 Millimeter of mercury | Standard Deviation 8.612 |
| GI262570 1.0mg | Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP) | SBP, Week 34 | 0.32 Millimeter of mercury | Standard Deviation 13.569 |
Primary
Number of Participants With Abnormal ECG Findings
A standardized 12-lead ECGs were recorded at pre-screening, and pre-dose, at Baseline/Day 1, Weeks 16, 34, and 52 or withdrawal and at the 4 week follow-up visit. Any conditions such as bundle branch block, repolarization, depolarization, abnormal sinus rhythms, atrial fibrillation etc. are considered to be clinically abnormal findings.
Time frame: Up to 4 weeks post-treatment (52 weeks)
Population: As Treated Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Abnormal ECG Findings | Week 34, Abnormal, clinically significant | 0 Participants |
| Placebo | Number of Participants With Abnormal ECG Findings | Week 52, Abnormal, not clinically significant | 10 Participants |
| Placebo | Number of Participants With Abnormal ECG Findings | Week 16, Abnormal, not clinically significant | 18 Participants |
| Placebo | Number of Participants With Abnormal ECG Findings | Week 34, Abnormal, not clinically significant | 12 Participants |
| Placebo | Number of Participants With Abnormal ECG Findings | Baseline, Abnormal, not clinically significant | 25 Participants |
| GI262570 0.5mg | Number of Participants With Abnormal ECG Findings | Week 16, Abnormal, not clinically significant | 16 Participants |
| GI262570 0.5mg | Number of Participants With Abnormal ECG Findings | Week 34, Abnormal, clinically significant | 0 Participants |
| GI262570 0.5mg | Number of Participants With Abnormal ECG Findings | Baseline, Abnormal, not clinically significant | 25 Participants |
| GI262570 0.5mg | Number of Participants With Abnormal ECG Findings | Week 52, Abnormal, not clinically significant | 18 Participants |
| GI262570 0.5mg | Number of Participants With Abnormal ECG Findings | Week 34, Abnormal, not clinically significant | 19 Participants |
| GI262570 1.0mg | Number of Participants With Abnormal ECG Findings | Week 52, Abnormal, not clinically significant | 22 Participants |
| GI262570 1.0mg | Number of Participants With Abnormal ECG Findings | Baseline, Abnormal, not clinically significant | 22 Participants |
| GI262570 1.0mg | Number of Participants With Abnormal ECG Findings | Week 16, Abnormal, not clinically significant | 21 Participants |
| GI262570 1.0mg | Number of Participants With Abnormal ECG Findings | Week 34, Abnormal, not clinically significant | 23 Participants |
| GI262570 1.0mg | Number of Participants With Abnormal ECG Findings | Week 34, Abnormal, clinically significant | 1 Participants |
Primary
Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment.
Time frame: Up to 4 weeks post treatment (52 weeks)
Population: As Treated Population consisted of all participants for whom no clear evidence was available of failure to take study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 75 Participants |
| Placebo | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 7 Participants |
| GI262570 0.5mg | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 68 Participants |
| GI262570 0.5mg | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 10 Participants |
| GI262570 1.0mg | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any AE | 71 Participants |
| GI262570 1.0mg | Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) | Any SAE | 6 Participants |
Primary
Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time
Clinical laboratory parameters: Alkaline phosphatase, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Total bilirubin, Cholesterol, Carbon dioxide content/Bicarbonate (CO2/HCO3), Creatinine, Glucose, Hemoglobin, Potassium, Low density lipid (LDL) cholesterol, Lymphocytes, Sodium, Segmented neutrophils, Platelet count, White blood cell (WBC) count were assessed for change in grade toxicities. Toxicities were graded as grade 1 to grade 4 in increasing order of severity of toxicity. Thus grade 4 indicating severe toxicity. Only those parameters with grade 3 and 4 toxicities are presented.
Time frame: Up to 4 weeks post-treatment (52 weeks)
Population: As Treated Population. Only those participants available at the specified time points for particular parameter were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | ALT, grade 4 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Total bilirubin, grade 4 | 12 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Segmented neutrophils, grade 4 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Sodium, grade 4 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Glucose, grade 3 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | AST, grade 4 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Platelet count, grade 4 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Glucose, grade 4 | 0 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Potassium, grade 4 | 1 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | AST, grade 3 | 4 Participants |
| Placebo | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | ALT, grade 3 | 4 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | AST, grade 3 | 2 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Hemaglobin, grade 3 | 1 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Potassium, grade 4 | 0 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Sodium, grade 4 | 1 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Segmented neutrophils, grade 4 | 0 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Platelet count, grade 4 | 0 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | AST, grade 4 | 0 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Total bilirubin, grade 4 | 17 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | ALT, grade 4 | 0 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Glucose, grade 3 | 0 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | ALT, grade 3 | 2 Participants |
| GI262570 0.5mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Glucose, grade 4 | 1 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Platelet count, grade 4 | 0 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | ALT, grade 3 | 5 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | ALT, grade 4 | 0 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | AST, grade 3 | 2 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | AST, grade 4 | 0 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Total bilirubin, grade 4 | 22 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Glucose, grade 3 | 0 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Glucose, grade 4 | 0 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Hemaglobin, grade 3 | 1 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Sodium, grade 4 | 1 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Segmented neutrophils, grade 4 | 0 Participants |
| GI262570 1.0mg | Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time | Potassium, grade 4 | 0 Participants |
Primary
Number of Participants With Fluid Retention Events
Fluid retention event was one of the AEs reported. AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time frame: Up to 4 weeks post-treatment (52 weeks)
Population: As Treated Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Fluid Retention Events | 0 Participants |
| GI262570 0.5mg | Number of Participants With Fluid Retention Events | 1 Participants |
| GI262570 1.0mg | Number of Participants With Fluid Retention Events | 1 Participants |
Primary
Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52
In ranked assessment (fibrosis and necroinflammation), available slides from each participant were evaluated as to whether one slide presents a globally more benign histopathology or whether the matched slides comprise globally equivalent histologic patterns. Subsequent data analysis revealed whether slides scored (within matched pairs of slides) as more benign occurred in different proportions of the Week 52 liver biopsies, according to treatment group. The number of participants with paired biopsies was based on the number with a Rank Assessment.
Time frame: Week 52
Population: MITT Population. Only those participants with paired biopsies at the indicated time point were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, better than screening | 13 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, same as screening | 35 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, worse than screening | 16 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, missing | 1 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, better than screening | 11 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, same as screening | 23 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, worse than screening | 31 Participants |
| Placebo | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, missing | 0 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, worse than screening | 17 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, worse than screening | 28 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, missing | 0 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, better than screening | 20 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, same as screening | 24 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, better than screening | 17 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, same as screening | 38 Participants |
| GI262570 0.5mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, missing | 0 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, worse than screening | 25 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, same as screening | 35 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, better than screening | 11 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Fibrosis, missing | 1 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, worse than screening | 22 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, same as screening | 23 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, better than screening | 27 Participants |
| GI262570 1.0mg | Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52 | Necrosis, missing | 0 Participants |
Comparison: Comparison for Ranked assessment (fibrosis)p-value: 0.6483Cochran-Mantel-Haenszel Test
Comparison: Comparison for Ranked assessment (necrosis)p-value: 0.1776Cochran-Mantel-Haenszel Test
Secondary
Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2
Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2 | 7283.04 milliliter per hour | Geometric Coefficient of Variation 64 |
| GI262570 0.5mg | Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2 | 5626.48 milliliter per hour | Geometric Coefficient of Variation 34 |
| GI262570 1.0mg | Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2 | 6617.76 milliliter per hour | Geometric Coefficient of Variation 55 |
| GI262570 1.0 mg Once Daily | Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2 | 7090.62 milliliter per hour | Geometric Coefficient of Variation 29 |
Secondary
Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2
Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: The Pharmacokinetic (PK) Parameter Population included all participants in the subset having the serial PK profiles performed at Week 2 and having sufficient data for the calculation of the PK parameters. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2 | 68.65 Hour nanograms per milliliter | Geometric Coefficient of Variation 64 |
| GI262570 0.5mg | Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2 | 88.87 Hour nanograms per milliliter | Geometric Coefficient of Variation 34 |
| GI262570 1.0mg | Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2 | 151.11 Hour nanograms per milliliter | Geometric Coefficient of Variation 55 |
| GI262570 1.0 mg Once Daily | Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2 | 141.03 Hour nanograms per milliliter | Geometric Coefficient of Variation 29 |
Secondary
DN Cmax of GI262570 on Week 2
Samples for Week 2 serial group were collected at 0 (pre-morning dose) 1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose) 1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | DN Cmax of GI262570 on Week 2 | 21.10 Nanograms per milliliter per mg | Geometric Coefficient of Variation 61 |
| GI262570 0.5mg | DN Cmax of GI262570 on Week 2 | 30.30 Nanograms per milliliter per mg | Geometric Coefficient of Variation 28 |
| GI262570 1.0mg | DN Cmax of GI262570 on Week 2 | 24.80 Nanograms per milliliter per mg | Geometric Coefficient of Variation 47 |
| GI262570 1.0 mg Once Daily | DN Cmax of GI262570 on Week 2 | 25.19 Nanograms per milliliter per mg | Geometric Coefficient of Variation 26 |
Secondary
Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2
Sample s for Week 2 serial group were collected at 0 (pre-morning dose )1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose )1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2 | 68.65 Hours nanograms per milliliter per mg | Geometric Coefficient of Variation 64 |
| GI262570 0.5mg | Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2 | 88.87 Hours nanograms per milliliter per mg | Geometric Coefficient of Variation 34 |
| GI262570 1.0mg | Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2 | 75.55 Hours nanograms per milliliter per mg | Geometric Coefficient of Variation 55 |
| GI262570 1.0 mg Once Daily | Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2 | 70.52 Hours nanograms per milliliter per mg | Geometric Coefficient of Variation 29 |
Secondary
GI262570 Serum Concentrations on Week 2, 16, 28, 40, and Week 52
Samples for Week 2 serial group were planned to be collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. For Weeks 16 and 40 samples were planned to be collected at 0 (pre-morning dose)1 and between 1.5-6 hour post-morning dose 2. For Weeks 28 and 52 samples were planned to be collected at 0 (pre-morning dose)1 and between 6-10 hour post-morning dose 2.
Time frame: Weeks 2, 16, 28, 40 and 52
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing. Data was not collected for this endpoint.
Secondary
Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2
Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmax | 21.10 Nanograms per milliliter | Geometric Coefficient of Variation 61 |
| Placebo | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmin | 0.69 Nanograms per milliliter | Geometric Coefficient of Variation 139 |
| GI262570 0.5mg | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmin | 0.19 Nanograms per milliliter | Geometric Coefficient of Variation 72 |
| GI262570 0.5mg | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmax | 30.30 Nanograms per milliliter | Geometric Coefficient of Variation 28 |
| GI262570 1.0mg | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmax | 49.60 Nanograms per milliliter | Geometric Coefficient of Variation 47 |
| GI262570 1.0mg | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmin | 1.54 Nanograms per milliliter | Geometric Coefficient of Variation 86 |
| GI262570 1.0 mg Once Daily | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmax | 50.38 Nanograms per milliliter | Geometric Coefficient of Variation 26 |
| GI262570 1.0 mg Once Daily | Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2 | Cmin | 0.18 Nanograms per milliliter | Geometric Coefficient of Variation 65 |
Secondary
Mean Change From Baseline in Measures of Insulin Resistance
Insulin resistance was measured using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Belfiore Insulin Sensitivity Index (ISI) and Quantitative Insulin Sensitivity Check Index (QUICKI). HOMA-IR = fasting plasma insulin\*fasting plasma glucose / 22.5 and ISI = 2 / \[(fasting plasma glucose from the participant / fasting plasma glucose normal reference range)\*( fasting plasma insulin from the participant / fasting plasma insulin normal reference range) + 1\] and QUICKI = 1/(log\[fasting plasma Insulin\] + log\[fasting plasma glucose\]). Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and Week 52
Population: As Treated Population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in Measures of Insulin Resistance | QUICKI | -0.0022 Units on a scale | Standard Deviation 0.01139 |
| Placebo | Mean Change From Baseline in Measures of Insulin Resistance | HOMA-IR | 0.9743 Units on a scale | Standard Deviation 6.28858 |
| Placebo | Mean Change From Baseline in Measures of Insulin Resistance | ISI | -0.0451 Units on a scale | Standard Deviation 0.24469 |
| GI262570 0.5mg | Mean Change From Baseline in Measures of Insulin Resistance | QUICKI | 0.0029 Units on a scale | Standard Deviation 0.01311 |
| GI262570 0.5mg | Mean Change From Baseline in Measures of Insulin Resistance | HOMA-IR | -1.3027 Units on a scale | Standard Deviation 4.73127 |
| GI262570 0.5mg | Mean Change From Baseline in Measures of Insulin Resistance | ISI | 0.0718 Units on a scale | Standard Deviation 0.28736 |
| GI262570 1.0mg | Mean Change From Baseline in Measures of Insulin Resistance | HOMA-IR | -1.8585 Units on a scale | Standard Deviation 3.95012 |
| GI262570 1.0mg | Mean Change From Baseline in Measures of Insulin Resistance | ISI | 0.1601 Units on a scale | Standard Deviation 0.24878 |
| GI262570 1.0mg | Mean Change From Baseline in Measures of Insulin Resistance | QUICKI | 0.0070 Units on a scale | Standard Deviation 0.01106 |
Secondary
Mean Change From Baseline in Serum ALT Levels
ALT was assessed as per upper limit of normal where the normal range was 0-48 international units per liter. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and Week 52
Population: MITT Population. Only those participants with data available at the indicated time points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Serum ALT Levels | 0.085 Per upper limit normal | Standard Deviation 0.8028 |
| GI262570 0.5mg | Mean Change From Baseline in Serum ALT Levels | -0.031 Per upper limit normal | Standard Deviation 0.6004 |
| GI262570 1.0mg | Mean Change From Baseline in Serum ALT Levels | -0.377 Per upper limit normal | Standard Deviation 1.0743 |
Secondary
Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52
FibroTest was for the assessment of fibrosis. Fibro test was calculated using an original combination of five highly concentrated serum biochemical markers; alpha-2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin and gammaglutamyltransferase. FibroTest scores range from 0.00 to 1.00 where 0.0-0.21 is no fibrosis and \>= 0.59 is cirrhosis. Acti-test was calculated using 6 serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT and alanine aminotransferase. ActiTest was used for the assessment of necroinflammatory activity. Test score ranges from 0.00 to 1.00, where 0.00-0.17 indicates no necrosis and \>= 0.61 indicates severe necrosis. Day 1 value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and Week 52
Population: MITT Population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | FibroSure: Fibrosis Score | -0.004 Scores on a scale | Standard Deviation 0.2187 |
| Placebo | Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | FibroSure: Activity Score | -0.010 Scores on a scale | Standard Deviation 0.1669 |
| GI262570 0.5mg | Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | FibroSure: Fibrosis Score | -0.064 Scores on a scale | Standard Deviation 0.3032 |
| GI262570 0.5mg | Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | FibroSure: Activity Score | -0.069 Scores on a scale | Standard Deviation 0.2899 |
| GI262570 1.0mg | Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | FibroSure: Fibrosis Score | -0.103 Scores on a scale | Standard Deviation 0.3044 |
| GI262570 1.0mg | Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52 | FibroSure: Activity Score | -0.132 Scores on a scale | Standard Deviation 0.2855 |
Secondary
Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52
Value at Day 1 visit (day of first dose) was considered as Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and Week 52
Population: MITT Population. Only those participants with data available at the indicated time point were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52 | -0.020 Log10 International unit per milliliter | Standard Deviation 0.4264 |
| GI262570 0.5mg | Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52 | -0.006 Log10 International unit per milliliter | Standard Deviation 0.376 |
| GI262570 1.0mg | Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52 | 0.040 Log10 International unit per milliliter | Standard Deviation 0.4803 |
Secondary
Mean Change From Screening in Metavir Scores at Week 52
Metavir activity score ranged from 0 to 3 (higher score indicates severe symptoms of necrosis). 0: Piecemeal necrosis (PMN) absent and lobular necrosis (LN) absent or slight, 1: PMN slight and LN moderate, 2: PMN moderate and LN severe, 3: PMN severe. Metavir fibrosis score ranged from 0 to 4 (higher score indicates severe symptoms of necrosis). 0: No fibrosis, 1: Portal fibrosis without septa, 2: Portal fibrosis with septa, 3: Septal fibrosis without cirrhosis, 4: Cirrhosis. Change from screening was calculated as the post screening assessment minus the screening assessment for a given parameter.
Time frame: Screening and Week 52
Population: MITT Population. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Screening in Metavir Scores at Week 52 | Metavir: Activity | 0.18 Scores on a scale | Standard Deviation 0.556 |
| Placebo | Mean Change From Screening in Metavir Scores at Week 52 | Metavir: Fibrosis | 0.02 Scores on a scale | Standard Deviation 0.604 |
| GI262570 0.5mg | Mean Change From Screening in Metavir Scores at Week 52 | Metavir: Activity | -0.01 Scores on a scale | Standard Deviation 0.722 |
| GI262570 0.5mg | Mean Change From Screening in Metavir Scores at Week 52 | Metavir: Fibrosis | 0.04 Scores on a scale | Standard Deviation 0.777 |
| GI262570 1.0mg | Mean Change From Screening in Metavir Scores at Week 52 | Metavir: Activity | -0.04 Scores on a scale | Standard Deviation 0.68 |
| GI262570 1.0mg | Mean Change From Screening in Metavir Scores at Week 52 | Metavir: Fibrosis | 0.13 Scores on a scale | Standard Deviation 0.653 |
Secondary
Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52
Ishak score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The necroinflammatory score is the combined score for necrosis and inflammation domains and ranged from 0 (best) to 14 (worst). Change from screening was calculated as the post screening assessment minus the screening assessment for a given parameter.
Time frame: Screening and Week 52
Population: MITT Population. Only those participants available at the specified time point were analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Necroinflammatory Score | 0.7 Scores on a scale | Standard Deviation 1.31 |
| Placebo | Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Fibrosis Score | 0.1 Scores on a scale | Standard Deviation 0.71 |
| GI262570 0.5mg | Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Necroinflammatory Score | 0.2 Scores on a scale | Standard Deviation 1.6 |
| GI262570 0.5mg | Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Fibrosis Score | 0.0 Scores on a scale | Standard Deviation 0.85 |
| GI262570 1.0mg | Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Necroinflammatory Score | -0.2 Scores on a scale | Standard Deviation 1.69 |
| GI262570 1.0mg | Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52 | Fibrosis Score | 0.2 Scores on a scale | Standard Deviation 0.7 |
Secondary
Median Change From Baseline in Serum ALT Over Time
ALT was assessed as per upper limit of normal where the normal range was 0-48 international units per liter. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and up to 4 weeks post-treatment (52 weeks)
Population: MITT Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 52 | 0.021 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 40 | -0.021 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 22 | 0.010 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 34 | -0.042 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 28 | -0.021 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 2 | -0.021 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 10 | -0.021 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 4 | -0.042 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 46 | -0.063 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Week 16 | 0.021 Per upper limit normal |
| Placebo | Median Change From Baseline in Serum ALT Over Time | Post-treatment | -0.042 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 28 | -0.146 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 2 | -0.083 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 4 | -0.063 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 10 | -0.063 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 22 | -0.146 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 16 | -0.125 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 34 | -0.188 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 40 | -0.104 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 46 | -0.146 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Week 52 | -0.083 Per upper limit normal |
| GI262570 0.5mg | Median Change From Baseline in Serum ALT Over Time | Post-treatment | -0.146 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 52 | -0.271 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 40 | -0.208 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 10 | -0.219 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 2 | -0.167 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 46 | -0.229 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 4 | -0.167 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 28 | -0.208 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 22 | -0.198 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Post-treatment | -0.229 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 34 | -0.271 Per upper limit normal |
| GI262570 1.0mg | Median Change From Baseline in Serum ALT Over Time | Week 16 | -0.208 Per upper limit normal |
Secondary
Median Change From Baseline in Serum HCV RNA Levels Over Time
Serum for HCV RNA levels were collected at pre-screen, Baseline, Week 28, Week 52, and at the 4 week follow up visit. Value at Day 1 visit (day of first dose) was considered as Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.
Time frame: Baseline and up to 4 weeks post-treatment (52 weeks)
Population: MITT Population. Only those participants available at the specified time points were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Median Change From Baseline in Serum HCV RNA Levels Over Time | Week 52 | -0.059 Log10 International unit per milliliter |
| Placebo | Median Change From Baseline in Serum HCV RNA Levels Over Time | Week 28 | 0.112 Log10 International unit per milliliter |
| Placebo | Median Change From Baseline in Serum HCV RNA Levels Over Time | Post-treatment | 0.024 Log10 International unit per milliliter |
| GI262570 0.5mg | Median Change From Baseline in Serum HCV RNA Levels Over Time | Week 52 | 0.034 Log10 International unit per milliliter |
| GI262570 0.5mg | Median Change From Baseline in Serum HCV RNA Levels Over Time | Week 28 | 0.011 Log10 International unit per milliliter |
| GI262570 0.5mg | Median Change From Baseline in Serum HCV RNA Levels Over Time | Post-treatment | 0.039 Log10 International unit per milliliter |
| GI262570 1.0mg | Median Change From Baseline in Serum HCV RNA Levels Over Time | Week 28 | 0.071 Log10 International unit per milliliter |
| GI262570 1.0mg | Median Change From Baseline in Serum HCV RNA Levels Over Time | Post-treatment | 0.026 Log10 International unit per milliliter |
| GI262570 1.0mg | Median Change From Baseline in Serum HCV RNA Levels Over Time | Week 52 | 0.013 Log10 International unit per milliliter |
Secondary
Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52
Progression was defined as an increase by at least one point in the fibrosis score. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score.
Time frame: Week 52
Population: MITT Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | 12 Participants |
| GI262570 0.5mg | Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | 14 Participants |
| GI262570 1.0mg | Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | 19 Participants |
Secondary
Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52
Regression was defined as a decrease by at least one point in the fibrosis score. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score.
Time frame: Week 52
Population: MITT Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | 11 Participants |
| GI262570 0.5mg | Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | 14 Participants |
| GI262570 1.0mg | Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52 | 9 Participants |
Secondary
Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52
No change was defined as having the same score at both Baseline and at Week 52. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score.
Time frame: Week 52
Population: MITT Population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52 | 41 Participants |
| GI262570 0.5mg | Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52 | 44 Participants |
| GI262570 1.0mg | Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52 | 43 Participants |
Secondary
Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2
Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | T1/2 | 3.33 hour |
| Placebo | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tmax | 2.00 hour |
| Placebo | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tlag | 0.000 hour |
| GI262570 0.5mg | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | T1/2 | 2.47 hour |
| GI262570 0.5mg | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tmax | 1.50 hour |
| GI262570 0.5mg | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tlag | 0.000 hour |
| GI262570 1.0mg | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tlag | 0.000 hour |
| GI262570 1.0mg | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | T1/2 | 2.54 hour |
| GI262570 1.0mg | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tmax | 1.75 hour |
| GI262570 1.0 mg Once Daily | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | T1/2 | 2.25 hour |
| GI262570 1.0 mg Once Daily | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tmax | 1.75 hour |
| GI262570 1.0 mg Once Daily | Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2 | Tlag | 0.000 hour |
Secondary
Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570
Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.
Time frame: At 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose on Week 2
Population: PK parameter Population. Initially the doses selected were twice daily, but after implementation of Amendment 4 the dose regimen was reduced to half the original dosing.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570 | 33440.98 milliliter | Geometric Coefficient of Variation 83 |
| GI262570 0.5mg | Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570 | 19971.49 milliliter | Geometric Coefficient of Variation 51 |
| GI262570 1.0mg | Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570 | 25616.42 milliliter | Geometric Coefficient of Variation 85 |
| GI262570 1.0 mg Once Daily | Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570 | 24355.48 milliliter | Geometric Coefficient of Variation 52 |