A Phase 2, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Activity of GS 9450 in Adults with Non-Alcoholic Steatohepatitis (NASH)

• Register: EUCTR
• Last refreshed on: 4 April 2022
• Main ID: EUCTR2008-002361-31-FR
• Date of registration: 27/06/2008
• Prospective Registration: Yes
• Primary sponsor: Gilead Sciences Incorporated
• Public title: A Phase 2, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Activity of GS 9450 in Adults with Non-Alcoholic Steatohepatitis (NASH)
• Scientific title: A Phase 2, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Activity of GS 9450 in Adults with Non-Alcoholic Steatohepatitis (NASH)
• Date of first enrolment: 09/09/2008
• Target sample size: 110
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2008-002361-31
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France

Key inclusion & exclusion criteria

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 ß-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)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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
a-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; a-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-TNFa) 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 all

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

Health Condition(s) or Problem(s) studied

Non-Alcoholic Steatohepatitis (NASH)
MedDRA version: 9.1 Level: LLT Classification code 10053219 Term: Non-alcoholic steatohepatitis

Intervention(s)

Product Name: N/A
Product Code: GS-9450
Pharmaceutical Form: Capsule*
CAS Number: 908253-63-4
Current Sponsor code: GS-9450
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1 -
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: N/A
Product Code: GS-9450
Pharmaceutical Form: Capsule*
CAS Number: 908253-63-4
Current Sponsor code: GS-9450
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: N/A
Product Code: GS-9450
Pharmaceutical Form: Capsule*
CAS Number: 908253-63-4
Current Sponsor code: GS-9450
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Product Name: N/A
Product Code: GS-9450
Pharmaceutical Form: Capsule*
CAS Number: 908253-63-4
Current Sponsor code: GS-9450
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: • To investigate the safety and tolerability of multiple oral doses of GS 9450 in subjects with NASH

Secondary Objective: • 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)

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, TNFa, 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, ?z, T1/2, AUCtau, Vdss/F (GS-9450 only) and CL/F (GS-9450 only).

Secondary ID(s)

GS-US-228-0101

Ethics review

Status: Approved
Approval date: 09/09/2008
Contact:

Results

• Results available: Yes
• Date Posted: 05/01/2017
• Date Completed: 05/08/2009
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2008-002361-31/results