Study to Assess the Efficacy, Safety and Tolerability of LCQ908 in NAFLD Patients

A Randomized, Multicenter, Double-blind, Placebo-controlled, Parallel-group, 24-week Pilot Study to Assess the Efficacy, Safety and Tolerability of LCQ908 in Patients With Non-alcoholic Fatty Liver Disease

The purpose of this study was to determine whether LCQ908 effectively lowers liver fat, as assessed by MRI and to assess its safety and tolerability profile in subjects with non-alcoholic fatty liver disease (NAFLD).

Study Overview

• Status: Completed
• Conditions: Non-alcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: placebo; Drug: LCQ908

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Novartis Investigative Site
  • California
    • San Diego, California, United States, 92114
      • Novartis Investigative Site
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • Novartis Investigative Site
    • Miami, Florida, United States, 33126
      • Novartis Investigative Site
    • Tamarac, Florida, United States, 33319
      • Novartis Investigative Site
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
      • Novartis Investigative Site
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • Novartis Investigative Site
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • Plano, Texas, United States, 75093
      • Novartis Investigative Site
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• History of liver steatosis during the preceding 24 months
• History of fasting TGs > 200 mg/dL (confirmed at screening).
• Liver fat ≥ 10% as determined by the central MRI laboratory.

• Subjects on the following medications can be included if these medications are medically necessary, cannot be stopped and the investigator feels their dose will remain stable for the duration of the double-blind treatment period:

  1. Stable dose of anti-diabetic medications (metformin and/or sulfonylureas) for at least 8 weeks prior to screening.
  2. Stable doses of beta-blockers and thiazide diuretics for at least 8 weeks prior to screening.
  3. Stable doses of fibrates, statins, niacin, ezetimibe for at least 8 weeks prior to screening.
  4. Stable dose of vitamin E in patients taking >200 IU/day for at least 6 months prior to screening.

Exclusion Criteria:

• Treatment with omega-3-acid ethyl esters or omega-3-polyunsaturated fatty acid (PUFA)-containing supplements > 200 mg per day within 8 weeks of screening.
• Treatment with antiretrovirals, tamoxifen, methotrexate, cyclophosphamide, isotretinoin, bile acid binding resins or pharmacologic doses of oral glucocorticoids (≥10 mg of prednisone per day or equivalent) within 8 weeks of screening.
• ALT or AST > 250 IU/L at the time of screening.
• History/current evidence of heavy alcohol use or alcoholism (> 21 drinks per week in men and > 14 drinks per week in women) over a 2-year period prior to screening.
• Presence of chronic liver disease, such as chronic hepatitis B and/or C, alcoholic liver disease, hemochromatosis, Wilson's disease, known cirrhosis.
• Platelet count <150,000 at screening.
• BMI >45 Kg/m2.

Other protocol defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Patients randomized to Placebo arm, received matching placebo to 5 mg, 10 mg and 20 mg pradigstat (LCQ908) once daily for 24 weeks. Each patient was to receive 3 tablets a day. All patients were required to remain on their American Heart Association (AHA) diet for the entire duration of the study.	Drug: placebo; Matching placebo of LCQ908 5 mg, 10 mg, 20 mg tablets.
Experimental: pradigastat (LCQ908) 5mg/10mg; Patients, randomized to pradigastat 5/10 mg, initially began with pradigastat (LCQ908) 5 mg once daily and then were up-titrated, if pradigastat (LCQ908) 5 mg once daily was tolerated, to pradigastat 10 mg once daily at Week 2. Total treatment duration was 24 weeks. Each patient was to receive 3 tablets a day. All patients were required to remain on their American Heart Association (AHA) diet for the entire duration of the study.	Drug: LCQ908; LCQ908 5 mg, 10 mg, 20 mg tablets; Other Names: pradigastat
Experimental: pradigastat (LCQ908) 10mg/20mg; Patients, randomized to pradigastat 10/20 mg, initially began with pradigastat (LCQ908) 10 mg once daily and then were up-titrated, if pradigastat (LCQ908) 10 mg once daily was tolerated, to pradigastat 20 mg once daily at Week 2. Total treatment duration was 24 weeks. Each patient was to receive 3 tablets a day. All patients were required to remain on their American Heart Association (AHA) diet for the entire duration of the study.	Drug: LCQ908; LCQ908 5 mg, 10 mg, 20 mg tablets; Other Names: pradigastat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24	Patients were to undergo MRI three times during the course of the study to assess liver fat. Baseline is defined as the value collected at Week -2 MRI assessment (approximately between Day -7 to -14).	From baseline to week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12	Patients were to undergo MRI three times during the course of the study to assess liver fat. Baseline is defined as the value collected at Week -2 MRI assessment (approximately between Day -7 to -14).	From baseline to week 12
Percentage of Responders at Week 12	The response criteria are defined as: a. A reduction of ≥ 30% from baseline in liver fat b. A reduction of ≥ 50% from baseline in liver fat c. Liver fat content < 10% d. Liver fat content < 5.6%. Percentage is calculated as (m/n)*100 where m: number of patients who are responders. n: number of patients with non-missing percent liver fat at that visit.	At week 12
Percentage of Responders at Week 24	The response criteria are defined as: a. A reduction of ≥ 30% from baseline in liver fat b. A reduction of ≥ 50% from baseline in liver fat c. Liver fat content < 10% d. Liver fat content < 5.6%. Percentage is calculated as (m/n)*100 where m: number of patients who are responders. n: number of patients with non-missing percent liver fat at that visit.	From baseline to week 24
Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6	Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate.	From Baseline to week 6
Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12	Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate.	From Baseline to week 12
Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24	Change from baseline ALT, AST and GGT values collected post-dose was analyzed using Mixed Model of Repeated Measurements (MMRM). Baseline is defined as the value collected at Week 0 (randomization). Treatment group and visit were fitted as factors and baseline was fitted as a continuous covariate.	From Baseline to week 24
Percentage of Patients With Normalized Liver Enzymes	Normalized liver enzymes defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 40 U/L. Normal/High categories at baseline are defined by criteria of normal. Better is defined as high' at baseline and 'normal' post-dose; Same is defined as 'normal' at baseline and 'normal' post-dose or 'high' at baseline and 'high' post-dose; Worse is defined as 'normal' at baseline and 'high' post-dose.	Baseline, week 6, week 12 and week 24
Percent Change From Baseline in Fasting Triglycerides	Blood samples were collected for a fasting triglycerides (TG) after a 10-hour (overnight) fast. Adjusted geometric means which is reported are calculated by back-transforming the adjusted means from the model and expressing as a percentage change from baseline. Baseline is defined as the value collected at Week 0 (randomization).	Baseline, 6, 12 and 24 weeks
Post-prandial Peak Triglycerides Over 0 - 8 Hours	Post-prandial peak triglycerides is reported as maximum triglyceride value over 0-8 hours. Adjusted geometric means which is reported are calculated by back-transforming the adjusted means from the model. Baseline is defined as the value collected at Week 0 (randomization).	Baseline, 6 and 24 weeks
Change From Baseline in Body Weight		Baseline, 12 and 24 weeks
Change From Baseline in Waist Circumference		Baseline, 12 and 24 weeks
Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability		24 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: March 12, 2013
• First Submitted That Met QC Criteria: March 12, 2013
• First Posted (Estimate): March 14, 2013

Study Record Updates

• Last Update Posted (Estimate): February 4, 2016
• Last Update Submitted That Met QC Criteria: January 5, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: NAFLD,; randomized,; Multi-center,; double-blind,; elevated triglycerides
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: CLCQ908A2216; 2013-000049-38 (EudraCT Number)