A Randomized, Double-blind, Placebo Controlled Study to Assess Efficacy, Safety and Tolerability of LCQ908 in Subjects With Familial Chylomicronemia Syndrome

Phase 3

Completed

Conditions: Familial Chylomicronemia Syndrome (FCS)

Interventions: Drug: LCQ908
Drug: Placebo

Registration Number: NCT01514461

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study is to determine whether LCQ908 is effective and safe in lowering triglycerides in subjects with Familial Chylomicronemia Syndrome (FCS) (Hyperlipoproteinemia \[HLP\] type I). Data from this study will be used to support a registration submission of LCQ908 20 mg and 40 mg as treatment of chylomicronemia in subjects with FCS (HLP Type 1).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 45

Inclusion Criteria

Written informed consent given before any assessment was performed for Period I.
Male and female patients ages at least 18 years of age.
Fasting triglyceride ≥ 8.4 mmol/L (750 mg/dL) at Screening.
An established diagnosis of FCS (HLP Type I) confirmed through ultracentrifugation or by documented medical history of a fasting triglyceride ≥ 8.4 mmol/L (750 mg/dL) and by documentation of any of the following at Screening or during the Screening Period:
- Confirmed homozygote or compound heterozygote for known loss-of-function mutations in Type I-causing genes (such as LPL, apo C II, GPIHBP1, or LMF1)
- Post heparin plasma LPL activity of ≤ 20% of normal
- Confirmed presence of LPL inactivating antibodies
History of pancreatitis.

Key

Exclusion Criteria

Current pancreatitis, pancreatitis was required to be inactive for at least 1 week prior to the screening Visit.
Treatment with fish oil preparations within 4 weeks prior to randomization.
Treatment with bile acid binding resins (i.e., colesevelam, etc.) within 4 weeks prior to randomization.
Treatment with fibrates within 4 weeks prior to randomization.
Glybera [alipogene tiparvovec (AAV1-LPLS447X)] gene therapy exposure within the two years prior to screening.
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
Any surgical or medical conditions, acute or unstable chronic disease which may, based on the investigator's opinion, jeopardize the patient in case of participation in the study or might significantly alter the absorption, distribution, metabolism or excretion of the study drug.
History of drug or alcohol abuse within the 12 months prior to randomization or evidence of such abuse at screening.
Evidence of liver disease or liver injury as indicated by abnormal liver function tests such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), or serum bilirubin.
Estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2 or history of chronic renal disease.
Participation in any clinical investigation within four (4) weeks prior to initial dosing or longer if required by local regulations, or any other limitation of participation based on local regulations.
History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive HCG laboratory test.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 100 days after discontinuation of investigational study drug.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LCQ908 20 mg	Placebo	In period II (0-12 weeks) double-blind treatment: one LCQ908 20 mg active tablet + one LCQ908 placebo matching to 40mg tablet, once daily. No dose titration allowed. In period III (12-52 weeks) double blind treatment: Without down titration, the period II dosing regimen will follow. Following decision to down titrate: one LCQ908 10 mg active tablet + one LCQ908 placebo matching to 40 mg tablet + one LCQ908 placebo matching to 10mg tablets, once daily. A low fat diet will be followed and recorded in patient diary.
LCQ908 20 mg	LCQ908	In period II (0-12 weeks) double-blind treatment: one LCQ908 20 mg active tablet + one LCQ908 placebo matching to 40mg tablet, once daily. No dose titration allowed. In period III (12-52 weeks) double blind treatment: Without down titration, the period II dosing regimen will follow. Following decision to down titrate: one LCQ908 10 mg active tablet + one LCQ908 placebo matching to 40 mg tablet + one LCQ908 placebo matching to 10mg tablets, once daily. A low fat diet will be followed and recorded in patient diary.
LCQ908 40 mg	Placebo	In period II (0-12 weeks) double-blind treatment: one LCQ908 40 mg active tablet + one LCQ908 placebo matching to 20mg tablet, once daily. No dose titration allowed. In period III (12-52 weeks) double blind treatment: Without down titration, the period II dosing regimen will follow. Following decision to down titrate: one LCQ908 20 mg active tablet + one LCQ908 placebo matching to 40 mg tablet + one LCQ908 placebo matching to 10mg tablets, once daily. A low fat diet will be followed and recorded in patient diary.
Placebo	Placebo	In period II (0-12 weeks) double-blind treatment: one LCQ908 placebo matching to 40mg tablet + one LCQ908 placebo matching to 20mg tablet, once daily. In period III (12-52 weeks) double blind treatment: Without down titration, the period II dosing regimen will follow. Following decision to down titrate: one LCQ908 placebo matching to 40mg tablet + one LCQ908 placebo matching to 20mg tablet + one LCQ908 placebo matching to 10mg tablets, once daily. A low fat diet will be followed and recorded in patient diary.
LCQ908 40 mg	LCQ908	In period II (0-12 weeks) double-blind treatment: one LCQ908 40 mg active tablet + one LCQ908 placebo matching to 20mg tablet, once daily. No dose titration allowed. In period III (12-52 weeks) double blind treatment: Without down titration, the period II dosing regimen will follow. Following decision to down titrate: one LCQ908 20 mg active tablet + one LCQ908 placebo matching to 40 mg tablet + one LCQ908 placebo matching to 10mg tablets, once daily. A low fat diet will be followed and recorded in patient diary.

Primary Outcome Measures

Name	Time	Method
Percent Change in Fasting Triglycerides From Baseline to 12 Weeks	Baseline to 12 weeks	Blood samples were collected for a fasting lipid panel, including triglycerides. If the 12-week value was missing, the measurement value at 12 weeks or the last available post-baseline measurement value during the double-blind treatment period was analyzed. Baseline is defined as the average of fasting triglyceride values taken at day -3 and day 1. Adjusted geometric means are calculated by back-transforming the adjusted means from the model and expressing as a percentage change from baseline.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Fasting Triglycerides	Baseline, 24 weeks, 52 weeks
Percent Change From Baseline for Postprandial Triglycerides Following the Standardized Meal Tolerance Test at Week 12	0-24 hours at Baseline, Week 12	Post prandial peak triglycerides - maximum triglyceride value over 0-24 hours Post prandial triglycerides AUC0-24 - area under the time curve for triglycerides over 0-24 Adjusted geometric means are calculated by back-transforming the adjusted means from the model and expressed as a percentage change from baseline. hours
Percentage of Patients Responding to Investigational Treatment by Achieving Final Fasting Triglycerides < 8.4 mmol/L (750 mg/dL)	12 weeks, 24 weeks, 52 weeks	Percentage calculated as (m/n)\*100 where m = number of patients who respond; n = the number of patients with non-missing fasting triglyceride.
Pharmacokinetics of LCQ908 - Trough Concentration (Cmin) and Observed Maximum Blood Concentration (Cmax)	0, 1, 2, 3, 4, 6, and 24 hours at Week 12	Lowest observed blood concentration (Cmin) and observed maximum blood concentration (Cmax) following drug administration derived from non-compartmental analysis using scheduled sampling time for the whole dataset.
Percentage of Patients Responding to Investigational Treatment by Achieving Fasting Triglycerides (TG) of at Least 40% From Baseline or Final Fasting TG < 8.4 mmol/L (750 mg/dL)	Baseline, 12 weeks, 24 weeks, 52 weeks	Percentage calculated as (m/n)\*100 where m = number of patients who respond; n = the number of patients with non-missing fasting triglyceride.
Percentage of Patients Responding to Investigational Treatment by Achieving Fasting Triglycerides (TG) of at Least 40% From Baseline	Baseline, 12 weeks, 24 weeks, 52 weeks	Percentage calculated as (m/n)\*100 where m = number of patients who respond; n = the number of patients with non-missing fasting triglyceride.
Percentage of Patients Achieving Fasting Triglycerides (TG) Target Thresholds	12 weeks, 24 weeks, 52 weeks	Percentage of patients reaching target values of \<1000 mg/dL or target values of \< 2000 mg/dL for fasting triglycerides is reported. Pecentage calculated as (m/n)\*100; where 'm' The number of patients who reach target values for fasting triglyceride, 'n' the number of patients with non-missing fasting triglyceride.
Number of Patients Reported With Any Adverse Event, Serious Adverse Event and Death	52 weeks
Pharmacokinetics of LCQ908- Area Under the Plasma Concentration Time Curve AUC (0-24hour)	0, 1, 2, 3, 4, 6, and 24 hours at Week 12	The area under the concentration-time curve from time zero to 24 hours after drug administration was calculated by using linear trapezoidal rule.
Pharmacokinetics of LCQ908- Time to Reach Maximum Concentration Following Drug Administration Tmax (Hours)	0, 1, 2, 3, 4, 6, and 24 hours at Week 12
Pharmacokinetics of LCQ908- Average Observed Blood Concentration (Cavg)	0, 1, 2, 3, 4, 6, and 24 hours at Week 12	Average observed blood concentration measured by (AUC0-24)/24.