Primary objective:- To determine the effect of LIK066 on Liver Function test after 12 weeks of treatmentSecondary objectives: - To determine the effect of LIK066 on intrahepatic lipid after 12 weeks of treatment- To determine the effect of LIK066 on…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in circulating alanine aminotransferase (ALT) levels
Secondary outcome
- Percent (%) Liver fat as measured by Magnetic Resonance Imaging (MRI-PDFF)
- Percent change in total body weight
- Enhanced liver fibrosis panel (ELF: PIIINP, TIMP-1, and Hyaluronic acid)
- Adverse events, safety laboratory tests including basic chemistry profile and
liver biochemical tests
- Cmax, Tmax, AUClast
- Circulating aspartate aminotrasferase (AST) levels
Background summary
Obesity has become a major global health problem that contributes causally to
and exacerbates many serious co-morbidities The presence of obesity and insulin
resistance, often with clinical features of the metabolic syndrome, leads to a
high-risk profile for the development of non-alcoholic fatty liver disease
(NAFLD). NAFLD encompasses a broad spectrum of disease severity, ranging from
isolated steatosis to its more
severe form with variable degrees of hepatocyte inflammation, necrosis and
liver fibrosis, known as nonalcoholic steatohepatitis (NASH), which can
progress to cirrhosis and end stage liver disease.
LIK066 is a potent inhibitor of the sodium glucose co-transporters 1 and 2
(SGLTs) that decreases absorption of glucose in the gut and reabsorption in the
kidney, and is investigated for the treatment of obesity and type 2 diabetes
mellitus.
The purpose of this study is to assess the effects of LIK066 on liver function
tests (LFT) and a variety of metabolic and inflammation biomarkers in patients
with NASH after 12 weeks of treatment. Data from this study will be used to
support further development of LIK066 in the treatment of patients with NASH.
Study objective
Primary objective:
- To determine the effect of LIK066 on Liver Function test after 12 weeks of
treatment
Secondary objectives:
- To determine the effect of LIK066 on intrahepatic lipid after 12 weeks of
treatment
- To determine the effect of LIK066 on total body weight after 12 weeks of
treatment
- To determine the effect of LIK066 on non-invasive markers of liver fibrosis
after 12 weeks of treatment
- To determine the safety and tolerability of LIK066
- To evaluate the pharmacokinetics (PK) of LIK066 in NASH patients
- To determine the effect of LIK066 on circulating aspartate aminotransferase
(AST) after 12 weeks of treatment
Exploratory objectives:
- To explore the effects of LIK066 on insulin sensitivity and glycemic control
- To explore the effects of LIK066 on markers of inflammation
- To explore the effects of LIK066 on changes in lipid metabolites
- To explore the effects of LIK066 on liver fibrosis biomarkers
- To explore the effects of LIK066 on pharmacogenetics in NASH patients
(optional)
- To explore the effects of LIK066 on other relevant biomarkers
- To explore the effects of LIK066 on body fat compartments
- To determine the effect of LIK066 on fasting lipid profile
- To explore the effect of LIK066 on liver inflammation and/or fibrosis
Study design
This is a non-confirmatory, multicenter, patient and investigator blinded,
randomized, placebo-controlled, parallel group study in patients with NASH. The
study will consist of a screening period up to 28 days, baseline period up to
14 days, treatment period of 12 weeks followed up by a study completion
evaluation approximately 28 days after the final drug administration.
Intervention
Study treatments are defined as:
- 50 mg LIK066 tablets
- 10 mg LIK066 tablet
- Matching placebo tablets
Initially, patients will be randomly assigned to one of the following two
treatments in a ratio of 2:1:
A: LIK066 150 mg
B: Matching placebo
Additional treatment arms (30 mg) may be introduced based on interim analysis
results or at the sponsor*s request, after 33 patients have been enrolled into
the initial 150 mg and matching placebo arms. If one additional dosing arm is
included, patients will be assigned to one of the following three treatments
(C, D or E) in a ratio of 2:4:1 using a new randomization schedule.
C: LIK066 150 mg
D: LIK066 30 mg
E: Matching placebo
Study burden and risks
Burden:
- time investment
- once daily intake of 3 oral LIK066 tablets or placebo during 12 weeks
- measurements including blood sampling and MRI
- compliance with strict lifestyle restrictions
- glucose measurements with a glucometer at home (possibly more than usual,
both before and after start of LIK066 if needed)
Potential risks:
- potential side effects of LIK066
- potential complaints caused by being fasted (especially in patients with type
2 diabetes mellitus), blood sample collection and MRI
Potential benefits:
- contributing in understanding (the treatment) of NASH
- possible positive effect on liver function (yet unknown)
- decrease in body weight
Lichtstrasse 35
Basel CH-4056
CH
Lichtstrasse 35
Basel CH-4056
CH
Listed location countries
Age
Inclusion criteria
Presence of NASH as demonstrated by one of the following:
either
Histologic confirmed NASH based on liver biopsy obtained 2 years or less before randomization with a fibrosis level of F1, F2 or F3, in the absence of a histological diagnosis of alternative chronic liver diseases AND ALT * 50 IU/L (males) or * 35 IU/L (females) at screening;Or
Phenotypic diagnosis of NASH based on presence of all three of the following at screening:
- ALT * 50 IU/L (males) or * 35 IU/L (females) AND
- BMI * 27 kg/m2 (in patients with a self-identified race other than Asian) or *23 kg/m2 (in patients with a self-identified Asian race) AND
- Diagnosis of Type 2 diabetes mellitus by HbA1C: * 6.5% and * 10%
Exclusion criteria
- Use of GLP-1 agonists such as liraglutide, exenatide, lixisenatide, albiglutide or dulaglutide; SGLT-2 inhibitors such as canagliflozin, empagliflozin or dapagliflozin; Thiazolidinediones (TZDs) such as pioglitazone; FXR agonists such as obeticholic acid (OCA) and any pharmacologically active weight-loss medications such as lorcaserin prior to 6 weeks of screening visit and up to end of study visit
- eGFR * 45ml/min/1.73m2 based on MDRD equation
- Patients on treatment with the following medicines unless they are on a constant dose for *3 months before randomization: anti-diabetic medications, insulin (if *25% change in dose),
beta-blockers, thiazide diuretics, fibrates, statins, niacin, ezetimibe, vitamin E (if doses > 400 IU/day; doses > 800 IU/day are prohibited), thyroid hormone, psychotropic medications, estrogen or estrogen containing birth control
- Current or history of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening (significant alcohol consumption is defined as more
than 20 g/day in females and more than 30 g/day in males, on average)
- Presence of cirrhosis on liver biopsy or clinical diagnosis of cirrhosis
- Type I diabetes and uncontrolled diabetes defined as HbAlc > 10 % within 60 days prior to enrollment
- Patients with contraindications to MRI imaging
- For those patients that have had a previous liver biopsy:
Significant weight loss (>15%) or change in clinical status (in the opinion of the investigator) since the diagnostic liver biopsy to screening
- History or presence of other concomitant liver diseases
- Clinical evidence of hepatic decompensation or severe liver impairment
- History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening and baseline
- History of inflammatory bowel disease
- History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study
- History of ketoacidosis, lactic acidosis, or hyperosmolar coma OR if occurring between Screening Visit and Randomization Visit.
- History of lower limb amputation (including toe amputation) OR if occurring between Screening Visit and Randomization Visit.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002046-71-NL |
| ClinicalTrials.gov | NCT03205150 |
| CCMO | NL63244.056.17 |