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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01811472
• Collaborator: (none)
• Enrollment: 52
• Locations: 11
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Non-alcoholic Fatty Liver Disease (NAFLD)	Drug: LCQ908; Drug: placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24 [From baseline to 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).

Secondary Outcome Measures

1. Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12 [From baseline to 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).

2. Percentage of Responders at Week 12 [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.

3. Percentage of Responders at Week 24 [From baseline to 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.

4. Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6 [From Baseline 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.

5. Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12 [From Baseline 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.

6. Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24 [From Baseline 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.

7. Percentage of Patients With Normalized Liver Enzymes [Baseline, week 6, week 12 and week 24]

   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.

8. Percent Change From Baseline in Fasting Triglycerides [Baseline, 6, 12 and 24 weeks]

   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).

9. Post-prandial Peak Triglycerides Over 0 - 8 Hours [Baseline, 6 and 24 weeks]

   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).

10. Change From Baseline in Body Weight [Baseline, 12 and 24 weeks]

11. Change From Baseline in Waist Circumference [Baseline, 12 and 24 weeks]

12. Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability [24 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Mobile	Alabama	United States	36608
2	Novartis Investigative Site	San Diego	California	United States	92114
3	Novartis Investigative Site	Gainesville	Florida	United States	32610-0277
4	Novartis Investigative Site	Miami	Florida	United States	33126
5	Novartis Investigative Site	Tamarac	Florida	United States	33319
6	Novartis Investigative Site	Honolulu	Hawaii	United States	96814
7	Novartis Investigative Site	Louisville	Kentucky	United States	40213
8	Novartis Investigative Site	Tupelo	Mississippi	United States	38801
9	Novartis Investigative Site	Houston	Texas	United States	77030
10	Novartis Investigative Site	Plano	Texas	United States	75093
11	Novartis Investigative Site	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01811472
• Other Study ID Numbers: CLCQ908A2216; 2013-000049-38
• First Posted: Mar 14, 2013
• Last Update Posted: Feb 4, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Multi-center,; randomized,; double-blind,; NAFLD,; elevated triglycerides
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease

Study Results

Participant Flow

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	20	11	21
COMPLETED	18	11	16
NOT COMPLETED	2	0	5

Baseline Characteristics

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	20	11	21	52
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.9 (7.69)	58.7 (6.56)	47.7 (11.76)	53.2 (10.32)
Sex: Female, Male (Count of Participants)
Female	10 50%	6 54.5%	10 47.6%	26 50%
Male	10 50%	5 45.5%	11 52.4%	26 50%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 24
Description	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).
Time Frame	From baseline to week 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with baseline and post-baseline value at week 24 are included in this analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	19	10	17
Least Squares Mean (95% Confidence Interval) [Percentage of liver fat]	0.00	-1.68	-2.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pradigastat (LCQ908) 5mg/10mg
	Comments	Hypothesis was tested at the 1-sided 5% significance level to assess if LCQ908 5mg/10mg was different from placebo.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The power calculation was largely driven by the maximum true response assumed in the candidate response shapes, which is a difference of -5.2% for pradigastat vs placebo for the primary endpoint.
Statistical Test of Hypothesis	p-Value	0.3128
	Comments
	Method	Mixed Model of Repeated Measurements
	Comments	Degrees of freedom are adjusted using the Kenward-Roger method.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.69
	Confidence Interval	(2-Sided) 90%; -4.46 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pradigastat (LCQ908) 10mg/20mg
	Comments	Hypothesis was tested at the 1-sided 5% significance level to assess if LCQ908 10mg/20mg was different from placebo.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The power calculation was largely driven by the maximum true response assumed in the candidate response shapes, which is a difference of -5.2% for pradigastat vs placebo for the primary endpoint.
Statistical Test of Hypothesis	p-Value	0.0457
	Comments
	Method	Mixed Model of Repeated Measurements
	Comments	Degrees of freedom are adjusted using the Kenward-Roger method.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.89
	Confidence Interval	(2-Sided) 90%; -5.25 to -0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Percentage of Fat in the Liver as Assessed Using MRI at Week 12
Description	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).
Time Frame	From baseline to week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with baseline and post-baseline value at week 12 are included in this analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	19
Least Squares Mean (90% Confidence Interval) [Percentage of liver fat]	-0.80	-1.71	-2.98

3. Secondary Outcome

Title	Percentage of Responders at Week 12
Description	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.
Time Frame	At week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing percent liver fat at week 12 were included in this endpoint analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	19
At least 30% reduction in percent liver fat	10.00	18.18	31.58
At least 50% reduction in percent liver fat	5.00	0.00	21.05
Liver fat content < 10%	5.00	18.18	36.84
Liver fat content <5.6%	0.00	0.00	21.05

4. Secondary Outcome

Title	Percentage of Responders at Week 24
Description	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.
Time Frame	From baseline to week 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing percent liver fat at week 24 were included in this endpoint analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	19	10	17
At least 30% reduction in percent liver fat	10.53	30.00	35.29
At least 50% reduction in percent liver fat	0.00	0.00	17.65
Liver fat content < 10%	5.26	20.00	52.94
Liver fat content <5.6%	0.00	0.00	17.65

5. Secondary Outcome

Title	Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 6
Description	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.
Time Frame	From Baseline to week 6

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at different timepoint were included in this endpoint analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	20
Liver enzyme: Alanine aminotransferase (ALT)	-2.6	1.4	-9.1
Liver enzyme: Aspartate aminotransferase (AST)	2.9	4.7	-2.5
Liver enzyme: Gamma glutamyl transferase (GGT)	-13.9	-7.0	-0.9

6. Secondary Outcome

Title	Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 12
Description	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.
Time Frame	From Baseline to week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at week 12 were included in this endpoint analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	20
Liver enzyme: Alanine aminotransferase (ALT)	-0.6	2.9	-3.7
Liver enzyme: Aspartate aminotransferase (AST)	5.7	8.9	-0.1
Liver enzyme: Gamma glutamyl transferase (GGT)	-0.4	-6.0	12.0

7. Secondary Outcome

Title	Change From Baseline Values for Alanine Aminotransferase (ALT) , Aspartate Aminotransferase (AST) and Gamma-glutamyl Transpeptidase (GGT) to Week 24
Description	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.
Time Frame	From Baseline to week 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at week 24 were included in this endpoint analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	20
Liver enzyme: Alanine aminotransferase (ALT)	-5.3	-1.0	-10.0
Liver enzyme: Aspartate aminotransferase (AST)	-1.8	2.5	-3.2
Liver enzyme: Gamma glutamyl transferase (GGT)	-11.6	-8.3	0.1

8. Secondary Outcome

Title	Percentage of Patients With Normalized Liver Enzymes
Description	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.
Time Frame	Baseline, week 6, week 12 and week 24

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing liver enzyme values at different timepoints were included in this endpoint analysis.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	20
Better, week 6	10.0	0.0	10.0
Same, week 6	85.0	90.9	85.0
Worse, week 6	5.0	9.1	5.0
Better, week 12	5.0	9.1	17.6
Same, week 12	90.0	72.7	64.7
Worse, week 12	5.0	18.2	17.6
Better, week 24	5.3	18.2	17.6
Same, week 24	89.5	72.7	58.8
Worse, week 24	5.3	9.1	23.5

9. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides
Description	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).
Time Frame	Baseline, 6, 12 and 24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing values at different timepoints were included in this endpoint analysis

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	21
Change From Baseline to week 6 (n= 20,11, 20)	-14.6	-16.0	3.2
Change From Baseline to week 12 (n = 20,11,17)	-7.3	-7.9	-15.8
Change From Baseline to week 24 (n= 19,11,17)	13.0	-10.0	-2.4

10. Secondary Outcome

Title	Post-prandial Peak Triglycerides Over 0 - 8 Hours
Description	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).
Time Frame	Baseline, 6 and 24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with non-missing values at different timepoints were included in this endpoint analysis

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	21
Baseline (n= 20, 11, 21)	394.0	370.2	375.9
Week 6 (n = 20,11,20)	336.0	309.7	374.1
Week 24 (n= 20, 11, 15)	401.5	305.7	351.8

11. Secondary Outcome

Title	Change From Baseline in Body Weight
Time Frame	Baseline, 12 and 24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with both baseline and post-baseline values at different timepoints were included in this endpoint analysis

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	21
Change from baseline to week 12 (n=20, 11, 17)	-1.3	-2.2	-2.4
Change from baseline to week 24 (n=18, 11, 17)	-1.1	-2.8	-2.5

12. Secondary Outcome

Title	Change From Baseline in Waist Circumference
Time Frame	Baseline, 12 and 24 weeks

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients to whom study treatment was assigned excluding patients who were miss-randomized and did not take investigational drug. Patients with both baseline and post-baseline values at different timepoints were included in this endpoint analysis

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	21
Change from baseline to week 12 (n=20, 11, 17)	-0.4	-3.7	-4.2
Change from baseline to week 24 (n=19, 11, 17)	-1.7	-3.7	-4.2

13. Secondary Outcome

Title	Number of Patients With Adverse Events, Serious Adverse Events (SAEs) and Death as Assessment of Safety and Tolerability
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Safety set (SAF) - All patients who received at least one dose of study drug and had at least 1 post-baseline safety assessment.

Arm/Group Title	Placebo	Pradigastat (LCQ908) 5mg/10mg	Pradigastat (LCQ908) 10mg/20mg
Arm/Group Description	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.	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.	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.
Measure Participants	20	11	21
Patients with any adverse event	14	9	20
Patients with at least one SAE	3	1	2
Death	0	0	0

Adverse Events

Adverse Event Reporting Description	Safety set (SAF) - All patients who received at least one dose of study drug and had at least 1 post-baseline safety assessment.
Arm/Group Title	Placebo		Pradigastat (LCQ908) 5mg /10 mg		Pradigastat (LCQ908) 10mg/20 mg		Pooled Pradigastat (LCQ908)
Arm/Group Description	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.		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.		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.		This arm included all patients randomized to pradigastat (LCQ908) 5mg/10 mg and pradigastat (LCQ908)10mg/20 mg
All Cause Mortality
	Placebo		Pradigastat (LCQ908) 5mg /10 mg		Pradigastat (LCQ908) 10mg/20 mg		Pooled Pradigastat (LCQ908)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Pradigastat (LCQ908) 5mg /10 mg		Pradigastat (LCQ908) 10mg/20 mg		Pooled Pradigastat (LCQ908)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		1/11 (9.1%)		2/21 (9.5%)		3/32 (9.4%)
General disorders
NON-CARDIAC CHEST PAIN	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC PROTRUSION	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
LUMBAR SPINAL STENOSIS	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Nervous system disorders
LUMBAR RADICULOPATHY	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
SPINAL CLAUDICATION	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
SYNCOPE	0/20 (0%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
Psychiatric disorders
DEPRESSION	0/20 (0%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
PANIC ATTACK	0/20 (0%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
Other (Not Including Serious) Adverse Events
	Placebo		Pradigastat (LCQ908) 5mg /10 mg		Pradigastat (LCQ908) 10mg/20 mg		Pooled Pradigastat (LCQ908)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/20 (70%)		9/11 (81.8%)		20/21 (95.2%)		29/32 (90.6%)
Blood and lymphatic system disorders
ANISOCYTOSIS	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
Cardiac disorders
PALPITATIONS	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Eye disorders
CONJUNCTIVITIS ALLERGIC	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Gastrointestinal disorders
ABDOMINAL DISCOMFORT	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
ABDOMINAL DISTENSION	3/20 (15%)		2/11 (18.2%)		3/21 (14.3%)		5/32 (15.6%)
ABDOMINAL PAIN	3/20 (15%)		1/11 (9.1%)		10/21 (47.6%)		11/32 (34.4%)
ABDOMINAL PAIN LOWER	0/20 (0%)		1/11 (9.1%)		2/21 (9.5%)		3/32 (9.4%)
ABDOMINAL PAIN UPPER	4/20 (20%)		3/11 (27.3%)		3/21 (14.3%)		6/32 (18.8%)
CONSTIPATION	4/20 (20%)		0/11 (0%)		3/21 (14.3%)		3/32 (9.4%)
DEFAECATION URGENCY	1/20 (5%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
DIARRHOEA	7/20 (35%)		6/11 (54.5%)		18/21 (85.7%)		24/32 (75%)
DYSPEPSIA	2/20 (10%)		3/11 (27.3%)		2/21 (9.5%)		5/32 (15.6%)
ERUCTATION	0/20 (0%)		1/11 (9.1%)		2/21 (9.5%)		3/32 (9.4%)
FAECES DISCOLOURED	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
FAECES HARD	2/20 (10%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
FAECES SOFT	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
FLATULENCE	4/20 (20%)		2/11 (18.2%)		3/21 (14.3%)		5/32 (15.6%)
GASTROINTESTINAL MOTILITY DISORDER	3/20 (15%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
GASTROINTESTINAL SOUNDS ABNORMAL	4/20 (20%)		1/11 (9.1%)		1/21 (4.8%)		2/32 (6.3%)
GASTROOESOPHAGEAL REFLUX DISEASE	1/20 (5%)		1/11 (9.1%)		1/21 (4.8%)		2/32 (6.3%)
GINGIVAL PAIN	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
NAUSEA	3/20 (15%)		4/11 (36.4%)		11/21 (52.4%)		15/32 (46.9%)
VOMITING	3/20 (15%)		2/11 (18.2%)		3/21 (14.3%)		5/32 (15.6%)
General disorders
CHILLS	0/20 (0%)		0/11 (0%)		2/21 (9.5%)		2/32 (6.3%)
INFLUENZA LIKE ILLNESS	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Infections and infestations
BRONCHITIS	0/20 (0%)		1/11 (9.1%)		2/21 (9.5%)		3/32 (9.4%)
LYME DISEASE	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
NASOPHARYNGITIS	4/20 (20%)		2/11 (18.2%)		0/21 (0%)		2/32 (6.3%)
PHARYNGITIS STREPTOCOCCAL	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
RESPIRATORY TRACT INFECTION	1/20 (5%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
UPPER RESPIRATORY TRACT INFECTION	1/20 (5%)		2/11 (18.2%)		0/21 (0%)		2/32 (6.3%)
URINARY TRACT INFECTION	0/20 (0%)		2/11 (18.2%)		0/21 (0%)		2/32 (6.3%)
Injury, poisoning and procedural complications
CONTUSION	2/20 (10%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
FALL	1/20 (5%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
INCISION SITE PAIN	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
LACERATION	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
LIGAMENT SPRAIN	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
STRESS FRACTURE	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Investigations
GAMMA-GLUTAMYLTRANSFERASE INCREASED	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
RETICULOCYTE COUNT INCREASED	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
Metabolism and nutrition disorders
DECREASED APPETITE	0/20 (0%)		2/11 (18.2%)		0/21 (0%)		2/32 (6.3%)
HYPOKALAEMIA	1/20 (5%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
TYPE 2 DIABETES MELLITUS	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/20 (5%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
BACK PAIN	2/20 (10%)		0/11 (0%)		2/21 (9.5%)		2/32 (6.3%)
FLANK PAIN	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
INTERVERTEBRAL DISC DEGENERATION	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
INTERVERTEBRAL DISC PROTRUSION	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
JOINT SWELLING	1/20 (5%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
LUMBAR SPINAL STENOSIS	1/20 (5%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
MUSCLE SPASMS	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
MUSCULOSKELETAL PAIN	1/20 (5%)		1/11 (9.1%)		2/21 (9.5%)		3/32 (9.4%)
MYALGIA	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
OSTEOARTHRITIS	0/20 (0%)		2/11 (18.2%)		1/21 (4.8%)		3/32 (9.4%)
PAIN IN EXTREMITY	1/20 (5%)		1/11 (9.1%)		1/21 (4.8%)		2/32 (6.3%)
SPINAL OSTEOARTHRITIS	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
Nervous system disorders
DIZZINESS	2/20 (10%)		1/11 (9.1%)		1/21 (4.8%)		2/32 (6.3%)
HEADACHE	1/20 (5%)		4/11 (36.4%)		1/21 (4.8%)		5/32 (15.6%)
HYPOAESTHESIA	2/20 (10%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
LUMBAR RADICULOPATHY	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
MIGRAINE	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Psychiatric disorders
ANXIETY	1/20 (5%)		0/11 (0%)		2/21 (9.5%)		2/32 (6.3%)
INSOMNIA	0/20 (0%)		0/11 (0%)		2/21 (9.5%)		2/32 (6.3%)
Renal and urinary disorders
HAEMATURIA	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
NEPHROLITHIASIS	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
URINE ODOUR ABNORMAL	1/20 (5%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
Reproductive system and breast disorders
MENOPAUSAL SYMPTOMS	0/20 (0%)		1/11 (9.1%)		0/21 (0%)		1/32 (3.1%)
Respiratory, thoracic and mediastinal disorders
ASTHMA	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
COUGH	1/20 (5%)		0/11 (0%)		3/21 (14.3%)		3/32 (9.4%)
DYSPNOEA EXERTIONAL	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
NASAL CONGESTION	1/20 (5%)		0/11 (0%)		1/21 (4.8%)		1/32 (3.1%)
OROPHARYNGEAL PAIN	0/20 (0%)		1/11 (9.1%)		1/21 (4.8%)		2/32 (6.3%)
PRODUCTIVE COUGH	0/20 (0%)		1/11 (9.1%)		1/21 (4.8%)		2/32 (6.3%)
PULMONARY MASS	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
SLEEP APNOEA SYNDROME	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Skin and subcutaneous tissue disorders
RASH	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)
Vascular disorders
HYPERTENSION	1/20 (5%)		0/11 (0%)		0/21 (0%)		0/32 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.