| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Alcoholic Steatohepatitis (NASH) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To investigate the safety and tolerability of multiple oral doses of GS 9450 in subjects with NASH |
|
| E.2.2 | Secondary objectives of the trial |
• To investigate the pharmacokinetics of multiple oral doses of GS 9450 and its metabolites in subjects with NASH
• To investigate the activity of multiple oral doses of GS 9450 in subjects with NASH, as evidenced by: (1) change from baseline in CK 18 fragments, (2) change from baseline in ALT, and (3) change from baseline in other non-invasive biomarkers (including metabolic markers)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in
this study.
• Male or female
• 18 through 75 years of age, inclusive
• ALT > 60 U/L at screening
• Fatty liver on screening ultrasound
• Biopsy-proven NASH diagnosed on liver biopsy that has been performed ≤ 12 months prior to screening. If there is no qualifying legacy biopsy, a liver biopsy must be performed during screening for study entry (all other eligibility criteria must be met
prior to procedure)
• Subjects with type 2 (non-insulin dependent) diabetes for < 10 years are eligible if
stably managed for at least 6 months prior to screening. Subjects receiving nonsulfonylurea, non-glitazone treatment for at least 6 months prior to screening are
allowed (sulfonylureas will be allowed if a forthcoming pharmacology study shows
no drug-drug interaction). Subjects may not initiate or change diabetes medications
during the study (from screening through the Follow-Up Week 4 Visit; see
Section 5.4 of the protocol for contingencies).
• Subjects should have a stable weight (no weight loss > 4%; see exclusions)
for 8 weeks prior to screening and should maintain consistent diet, food intake, and
physical exercise during the study. Pre-existing weight reduction programs should
be stably managed without change during the study (from screening through the
Follow-up Week 4 Visit). Study participants are asked to defer initiation of a new
weight reduction program until completion of this study.
• Negative serum β-HCG pregnancy test (for females < 60 years old; testing not
required for those who are surgically sterile [hysterectomy, tubal ligation,
oophorectomy])
• Creatinine clearance (CLcr) ≥ 70 mL/min, as calculated by the Cockcroft-Gault
equation using lean body weight (LBW):
(140-age in years) (LBW [kg])/ (72) (serum creatinine [mg/dL])
(Note: multiply estimated rate by 0.85 for women)
where:
Age is calculated in years, and serum creatinine is the subject’s measured serum
creatinine (in mg/dL).
LBW is the subject’s lean body weight in kilograms, calculated as:
Men: 50 + 2.3*[(height in cm – 152.4) / 2.54] OR 50 + 2.3*(height in inches – 60)
Women: 45.5 + 2.3*[(height in cm – 152.4) / 2.54] OR 45.5 + 2.3*(height in inches –
60)
If a subject’s height is less than or equal to 152.4 cm (60 inches), then his LBW is 50 kg
and her LBW is 45.5 kg. If the subject’s actual body weight is less than his or her
calculated LBW, then the subject’s actual weight should be used in place of his/her LBW.
• Adequate hematologic function at screening (absolute neutrophil count ≥ 1,500/mm3; hemoglobin ≥ 11.0 g/dL; platelet count ≥ 75,000/mm3)
• Willing and able to provide written informed consent
• Stable therapy for at least 3 months prior to screening if on the following medications:
HMG CoA reductase inhibitors, niacin, or fibrates (including gemfibrozil) for
hyperlipidemia; vitamin E; angiotensin receptor blockers; or drugs possibly associated with hepatotoxicity (isoniazid, itraconazole, ketoconazole, rifabutin, rifampin, and other agents with similar potential) |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this
study.
• Pregnant women, women who are breast feeding or who believe they may wish to
become pregnant during the course of the study.
• Males and females of reproductive potential who are not willing to use an effective
method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used in combination with one other form of contraception.
• Where required by local law or regulation, the participation of female subjects may be limited to women of non-childbearing potential or, if deemed appropriate, to males
only in that country
• A > 4% decrease in weight within 8 weeks of screening.
• Diagnosis of type 1 (insulin-dependent) diabetes mellitus
• Presence of diabetic peripheral neuropathy or gastroparesis or duration of type
2 diabetes ≥ 10 years
• Currently receiving sulfonylureas or glitazones (sulfonylureas will be allowed if a
forthcoming pharmacology study shows no drug-drug interaction)
• Have received glitazones within 6 months prior to screening
• Cirrhosis or decompensated liver disease at screening, defined as direct (conjugated) bilirubin > 1.5 × upper limit of the normal range (ULN), prothrombin time
> 1.5 × ULN, platelets < 75,000/mm3, serum albumin < 3.0 g/dL, or prior history of
clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal
hemorrhage)
• Evidence of hepatocellular carcinoma (HCC) at screening, as determined by an
α-fetoprotein level > 50 ng/mL or other standard of care measure
• Serological evidence of infection with human immunodeficiency virus (HIV),
hepatitis C virus (HCV), or hepatitis B virus (HBV)
• Presence of other forms of liver disease (including, but not limited to, alcoholic liver
disease; viral or autoimmune hepatitis; α-1-antitrypsin deficiency; hemochromatosis;
Wilson’s disease; primary biliary cirrhosis; primary sclerosing cholangitis; prior
exposure to organic solvents such as carbon tetrachloride; drug-induced liver disease;
or other metabolic, hereditary or infectious liver disease)
• History of hemochromatosis or iron overload, as defined by presence of
3 + or 4+ stainable iron on liver biopsy
• History of excessive alcohol ingestion, averaging > 30 gm/day (3 drinks/day) in the
previous 2 years, or current alcohol intake averaging > 20 gm/day (2 drinks/day) for
females and > 30 gm/day (3 drinks/day) for males
• History of or current binge drinking
• History of acute substance abuse within one year of screening
• History of or currently ingesting drugs possibly associated with hepatic steatosis
within the past year (amiodarone, diltiazem, tamoxifen, systemic glucocorticoids,
anabolic steroids, high-dose estrogens [contraceptives and hormone replacement
therapy are allowed], methotrexate, valproic acid, or perhexiline)
• History of ingesting drugs that may improve NASH and associated fibrosis (orlistat,
sibutramine, and other weight loss drugs, S-adenosyl-L-methionine, betaine, and
urosodeoxycholic acid) within 3 months prior to screening
• History of ingesting anti-tumor necrosis factor (anti-TNFα) drugs or
immunomodulators within 3 months prior to screening
• History of total parenteral nutrition within the past 6 months
• History of gastroplasty, jejunoileal bypass, or jejunocolonic bypass surgery
• Prior or current malignancy of any organ system and skin cancer (previously excised
basal cell carcinoma is allowed)
• Acute ongoing infection, or symptoms of infection (including mononucleosis and
varicella-zoster virus infection)
• Presence of inflammatory bowel disease or significant gastrointestinal disease that
would interfere with absorption of oral medications
• Presence of significant systemic or major illnesses other than liver disease that, in the opinion of the Investigator, would preclude treatment and adequate follow-up
(examples are provided in the Study Protocol)
• Clinically significant abnormalities on screening ECG (atrial fibrillation/flutter, S-T
elevation consistent with ischemia, evolving acute myocardial infarction, second
degree atrioventricular block Mobitz II, complete heart block, atrioventricular
dissociation, ventricular arrythmias, prolonged Q-T interval ≥ 500 msec) or other
ECG findings that the investigator considers as a safety risk
• History of solid organ or bone marrow transplantation
• History of major surgery within one year of screening
• Known hypersensitivity to the study drugs, the metabolites or formulation excipients
• Any other condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
Safety Endpoints
The primary safety endpoint will evaluate the tolerability of multiple oral doses of
GS-9450. This endpoint will be assessed using treatment-limiting adverse events or
laboratory abnormalities that require premature discontinuation from the study.
Activity Endpoints
The primary activity endpoints are the following at Week 4:
• Change (absolute, percent) from baseline in CK-18 fragments, ALT, and AST levels;
Additionally, change from baseline in non-invasive markers (C-peptide, free fatty acids, adiponectin, IL-6, TNFα, FibroTest, high-sensitivity C- reactive protein) will be
evaluated.
The following endpoints, which may affect activity, will be evaluated at Week 4:
• change in body weight and BMI from baseline; and
• change in serum lipid profile from baseline.
Pharmacokinetic Endpoints
The primary pharmacokinetic endpoints of this study are to characterize the plasma
pharmacokinetic parameters of GS-9450 and metabolites following multiple doses of
GS-9450. The pharmacokinetic parameter endpoints to be evaluated are Week 2-4 Cmax, Tmax, Cmin, λz, T1/2, AUCtau, Vdss/F (GS-9450 only) and CL/F (GS-9450 only). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LPLV is defined as the last follow-up visit (week 4 Off-Treatment Follow-up Assessment) for the last patient.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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