Safety, Tolerability and Efficacy of Nidufexor in Patients With Diabetic Nephropathy

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03804879
• Collaborator: (none)
• Enrollment: 83
• Locations: 18
• Arms: 2
• Actual Duration (Months): 28.5
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Nidufexor addresses fibrosis, oxidative stress, inflammation and cell death, and therefore has the potential to improve the management of diabetic kidney disease when added to the standard of care (SoC) (angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)).

This non-confirmatory Phase 2 study was designed to determine the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of nidufexor in combination with ACEI or ARB at a dose level that is SoC as judged by the study doctor in patients with type 2 diabetes and nephropathy.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Nephropathy	Drug: Nidufexor; Other: Placebo; Drug: Standard of Care (SoC)	Phase 2

Detailed Description

This was a non-confirmatory, multicenter, patient- and investigator-blinded, randomized, and placebo-controlled, proof-of concept trial assessing nidufexor vs. placebo in patients receiving standard of care (optimal tolerated doses of ARB or ACEI) for diabetic nephropathy due to type 2 diabetes.

The study consisted of three distinct study periods:

Screening (Day -30 to Day-1): lasted up to a maximum of 30 days and comprised a screening / baseline assessment. This visit was used to confirm that the study inclusion and exclusion criteria were met and served as baseline assessment prior to randomization. Participant randomization occurred prior to day 1 as soon as participant eligibility was confirmed.

Treatment period (Day 1-168): Participants were randomized in a 1:1 ratio to receive nidufexor 50 mg or placebo once daily for 24 weeks. Nidufexor and placebo were given in addition to SoC (optimal tolerated doses of ARB or ACEI).

End of Study (EOS) and Safety follow-up (Day 169 to Day 197): Study assessments were performed until the EOS visit (Day 169). Post Study Safety Contact occurred approximately 28 days after discontinuing study treatment until day 197.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Patient-and-physician Blinded, Placebo-controlled, 24-week Study to Assess the Safety, Tolerability and Efficacy of LMB763 in Patients With Diabetic Nephropathy
• Actual Study Start Date: Dec 17, 2018
• Actual Primary Completion Date: May 3, 2021
• Actual Study Completion Date: May 3, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LMB763 50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Drug: Nidufexor; 50 mg (two 25 mg) LMB763 capsules for oral administration; Other Names: LMB763 ; Drug: Standard of Care (SoC); Optimal tolerated doses of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)
Placebo Comparator: Placebo Placebo was orally administered once daily for 24 weeks in addition to SoC.	Other: Placebo; Placebo capsules for oral administration; Drug: Standard of Care (SoC); Optimal tolerated doses of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)

Outcome Measures

Primary Outcome Measures

1. Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) [Baseline and days 14, 29, 57, 85, 113, 141 and 169]

   UACR is a ratio between albumin and creatinine, and it estimates 24-hour urine albumin excretion. UACR (mg/mmol) = urine albumin [mg/L] / urine creatinine [mmol/L]. UACR was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.

2. Ratio to Baseline in 24 Hour Urinary Albumin at Week 24 (Day 169) [Baseline and day 169]

   Albuminuria describes the existence of albumin in the urine and the gold-standard to assess albuminuria is 24-hour urinary albumin excretion (milligram/24 hours). An analysis of covariance (ANCOVA) with treatment as the classification factor and log-transformed baseline as the covariate was conducted for log-transformed ratio to baseline 24-hour urinary albumin excretion. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.

3. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 197 days]

   Number of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory values qualifying and reported as AEs. The category Number of participants with AEs includes also the number of participants with SAEs. The number of participants in each category is reported in the table.

Secondary Outcome Measures

1. Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) [Baseline and days 14, 29, 57, 85, 113, 141 and 169]

   Estimate Glomerular Filtration Rate (GFR) calculates estimated GFR (eGFR) from serum creatinine levels to assess kidney function. eGFR (milliliter/minute) was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A higher score in the ratio to baseline indicates improvement.

2. Maximum Peak Observed Concentration (Cmax) of LMB763 [pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14]

   Pharmacokinetic (PK) parameters were calculated based on LMB763 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Cmax was determined using non-compartmental methods. No methods for imputation of missing data were used.

3. Time to Reach Maximum Blood Concentrations (Tmax) of LMB763 [pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14]

   Pharmacokinetic (PK) parameters were calculated based on LMB763 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Tmax was determined using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment). No methods for imputation of missing data were used.

4. Area Under the Blood Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of LMB763 [pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14]

   Pharmacokinetic (PK) parameters were calculated based on LMB763 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUClast was determined using non-compartmental methods. No methods for imputation of missing data were used.

5. Ratio to Baseline in Free Water Clearance [Baseline and day 169]

   The free water clearance (mL/min) was calculated using the following formula: (Total Volume (mL) / Elapsed Date & Time (min)) * (1-24 hr Urine Osmolality (mOsmol/kg)/ Serum Osmolality (mOsmol/kg)) The result of free water clearance was rounded to one decimal place prior to statistical analysis. An analysis of covariance (ANCOVA) with treatment as the classification factor and log-transformed baseline as the covariate was conducted for log-transformed ratio to baseline free water clearance. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A higher score in the ratio to baseline indicates improvement.

6. Ratio to Baseline in Lipoprotein A at Day 85 [Baseline and day 85]

   Lipoprotein A (gram/liter) is a component of the lipid profile which is a panel of blood tests used to find abnormalities in lipids. Ratio to baseline in Lipoprotein A was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.

7. Ratio to Baseline in Lipoprotein A at Day 169 [Baseline and day 169]

   Lipoprotein A (gram/liter) is a component of the lipid profile which is a panel of blood tests used to find abnormalities in lipids. Ratio to baseline in Lipoprotein A was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.

8. Percent Change From Baseline in Weight [Baseline and days 14, 29, 57, 85, 113, 141 and 169]

   Change from baseline in weight was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A negative score in the percent change from baseline indicates improvement.

9. Percent Change From Baseline in Body Mass Index (BMI) [Baseline and days 14, 29, 57, 85, 113, 141 and 169]

   BMI was determined by height and weight measurements: Body weight (kg)/ [Height (m)]^2. Change from baseline in BMI was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A negative score in the percent change from baseline indicates improvement.

10. Change From Baseline in Waist-to-hip Ratio [Baseline and days 14, 29, 57, 85, 113, 141 and 169]

    Waist-to-hip ratio was derived using waist circumference and hip circumference, which was measured at the greatest protrusion of the buttocks. Change from baseline in waist-to-hip ratio was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A negative score in the change from baseline indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male/female patients, 18-75 years

• Written informed consent

• Diagnosis of Type 2 diabetes mellitus, with diagnosis made at least 6 months prior to screening

• Diabetic nephropathy as evidenced by Urine albumin-Cr ratio (UACR) ≥300 mg/g Cr at screening while receiving a dose of angiotensin converting enzyme inhibitor or angiotensin receptor blocker that is the standard of care as judged by the study doctor.

Exclusion Criteria:

• History of type 1 diabetes mellitus

• Severe renal impairment manifesting as serum creatinine eGFR < 30 mL/min/1.73 m^2 at screening

• Pregnant or nursing (lactating) women

• Women of child-bearing potential, unless they are using basic methods of contraception during dosing of study treatment

• Uncontrolled diabetes mellitus at screening

• History or current diagnosis of ECG abnormalities prior to first study dose

• History of kidney disease other than diabetic nephropathy at screening

• Uncontrolled hypertension at screening

• Use of prohibited medications, including but not limited to GLP-1 agonists and SGLT2 inhibitors.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Miami Lakes	Florida	United States	33014
2	Novartis Investigative Site	Albany	New York	United States	12206
3	Novartis Investigative Site	Norman	Oklahoma	United States	73069
4	Novartis Investigative Site	El Paso	Texas	United States	79935
5	Novartis Investigative Site	Sugar Land	Texas	United States	77479
6	Novartis Investigative Site	Caba	Buenos Aires	Argentina	1407
7	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1056ABJ
8	Novartis Investigative Site	Buenos Aires		Argentina	C1120AAC
9	Novartis Investigative Site	Praha		Czechia	12808
10	Novartis Investigative Site	Essen	Nordrhine Westphalia	Germany	45136
11	Novartis Investigative Site	Berlin		Germany	10787
12	Novartis Investigative Site	Elsterwerda		Germany	04910
13	Novartis Investigative Site	Amman		Jordan	11941
14	Novartis Investigative Site	Ashrafieh		Lebanon
15	Novartis Investigative Site	Saida		Lebanon	652
16	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
17	Novartis Investigative Site	Kocaeli		Turkey	41380
18	Novartis Investigative Site	Talas / Kayseri		Turkey	38039

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Oct 27, 2020
• Statistical Analysis Plan - Jul 23, 2021

More Information

Additional Information:

• A Plain Language Trial Summary is available on novctrd.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03804879
• Other Study ID Numbers: CLMB763X2202; 2018-002491-40
• First Posted: Jan 15, 2019
• Last Update Posted: Aug 10, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: diabetes
• Additional relevant MeSH terms: Kidney Diseases; Diabetic Nephropathies

Study Results

Participant Flow

Recruitment Details	Participants were recruited from 18 sites in 7 countries.
Pre-assignment Detail	Participants underwent a Screening period of up to 30 days which included screening and baseline assessments.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Period Title: Overall Study
STARTED	41	42
Pharmacokinetics (PK) Analysis Set	41	0
Pharmacodynamics (PD) Analysis Set	41	41
COMPLETED	25	29
NOT COMPLETED	16	13

Baseline Characteristics

Arm/Group Title	LMB763	Placebo	Total
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.	Total of all reporting groups
Overall Participants	41	42	83
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.8 (8.95)	61.6 (8.36)	61.2 (8.61)
Sex: Female, Male (Count of Participants)
Female	13 31.7%	10 23.8%	23 27.7%
Male	28 68.3%	32 76.2%	60 72.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 2.4%	1 1.2%
White	41 100%	41 97.6%	82 98.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR)
Description	UACR is a ratio between albumin and creatinine, and it estimates 24-hour urine albumin excretion. UACR (mg/mmol) = urine albumin [mg/L] / urine creatinine [mmol/L]. UACR was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.
Time Frame	Baseline and days 14, 29, 57, 85, 113, 141 and 169

Outcome Measure Data

Analysis Population Description

All randomized participants. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41	42
Day 14	0.90	1.06
Day 29	0.83	1.00
Day 57	0.85	1.05
Day 85	0.84	1.07
Day 113	0.87	1.07
Day 141	0.84	1.15
Day 169	0.74	0.92

2. Primary Outcome

Title	Ratio to Baseline in 24 Hour Urinary Albumin at Week 24 (Day 169)
Description	Albuminuria describes the existence of albumin in the urine and the gold-standard to assess albuminuria is 24-hour urinary albumin excretion (milligram/24 hours). An analysis of covariance (ANCOVA) with treatment as the classification factor and log-transformed baseline as the covariate was conducted for log-transformed ratio to baseline 24-hour urinary albumin excretion. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.
Time Frame	Baseline and day 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. Only participants with a value at both baseline and at Day 169 were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	17	21
Least Squares Mean (80% Confidence Interval) [Ratio to baseline]	0.58	0.91

3. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Number of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory values qualifying and reported as AEs. The category Number of participants with AEs includes also the number of participants with SAEs. The number of participants in each category is reported in the table.
Time Frame	From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 197 days

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41	42
AEs	29 70.7%	25 59.5%
SAEs	2 4.9%	2 4.8%

4. Secondary Outcome

Title	Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR)
Description	Estimate Glomerular Filtration Rate (GFR) calculates estimated GFR (eGFR) from serum creatinine levels to assess kidney function. eGFR (milliliter/minute) was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A higher score in the ratio to baseline indicates improvement.
Time Frame	Baseline and days 14, 29, 57, 85, 113, 141 and 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41	41
Day 14	0.95	0.96
Day 29	0.94	0.94
Day 57	0.98	0.96
Day 85	0.97	0.94
Day 113	0.96	0.94
Day 141	0.98	0.93
Day 169	0.93	0.93

5. Secondary Outcome

Title	Maximum Peak Observed Concentration (Cmax) of LMB763
Description	Pharmacokinetic (PK) parameters were calculated based on LMB763 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Cmax was determined using non-compartmental methods. No methods for imputation of missing data were used.
Time Frame	pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set

Arm/Group Title	LMB763
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41
Day 1	1090 (665)
Day 14	1300 (691)

6. Secondary Outcome

Title	Time to Reach Maximum Blood Concentrations (Tmax) of LMB763
Description	Pharmacokinetic (PK) parameters were calculated based on LMB763 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. Tmax was determined using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment). No methods for imputation of missing data were used.
Time Frame	pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set

Arm/Group Title	LMB763
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41
Day 1	3.25
Day 14	2

7. Secondary Outcome

Title	Area Under the Blood Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of LMB763
Description	Pharmacokinetic (PK) parameters were calculated based on LMB763 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUClast was determined using non-compartmental methods. No methods for imputation of missing data were used.
Time Frame	pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set

Arm/Group Title	LMB763
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41
Day 1	3710 (2510)
Day 14	4850 (2910)

8. Secondary Outcome

Title	Ratio to Baseline in Free Water Clearance
Description	The free water clearance (mL/min) was calculated using the following formula: (Total Volume (mL) / Elapsed Date & Time (min)) * (1-24 hr Urine Osmolality (mOsmol/kg)/ Serum Osmolality (mOsmol/kg)) The result of free water clearance was rounded to one decimal place prior to statistical analysis. An analysis of covariance (ANCOVA) with treatment as the classification factor and log-transformed baseline as the covariate was conducted for log-transformed ratio to baseline free water clearance. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A higher score in the ratio to baseline indicates improvement.
Time Frame	Baseline and day 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. Only participants with a value at both baseline and at Day 169 were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	8	11
Least Squares Mean (80% Confidence Interval) [Ratio]	0.97	0.97

9. Secondary Outcome

Title	Ratio to Baseline in Lipoprotein A at Day 85
Description	Lipoprotein A (gram/liter) is a component of the lipid profile which is a panel of blood tests used to find abnormalities in lipids. Ratio to baseline in Lipoprotein A was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.
Time Frame	Baseline and day 85

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	19	24
Least Squares Mean (80% Confidence Interval) [Ratio]	0.72	0.95

10. Secondary Outcome

Title	Ratio to Baseline in Lipoprotein A at Day 169
Description	Lipoprotein A (gram/liter) is a component of the lipid profile which is a panel of blood tests used to find abnormalities in lipids. Ratio to baseline in Lipoprotein A was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A lower score in the ratio to baseline indicates improvement.
Time Frame	Baseline and day 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	12	19
Least Squares Mean (80% Confidence Interval) [Ratio to baseline]	0.75	0.89

11. Secondary Outcome

Title	Percent Change From Baseline in Weight
Description	Change from baseline in weight was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A negative score in the percent change from baseline indicates improvement.
Time Frame	Baseline and days 14, 29, 57, 85, 113, 141 and 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41	41
Day 14	-0.08	-0.13
Day 29	-0.57	-0.03
Day 57	-0.69	-0.24
Day 85	-0.41	0.08
Day 113	-0.51	0.21
Day 141	-0.80	0.43
Day 169	-0.61	0.55

12. Secondary Outcome

Title	Percent Change From Baseline in Body Mass Index (BMI)
Description	BMI was determined by height and weight measurements: Body weight (kg)/ [Height (m)]^2. Change from baseline in BMI was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A negative score in the percent change from baseline indicates improvement.
Time Frame	Baseline and days 14, 29, 57, 85, 113, 141 and 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41	41
Day 14	-0.01	-0.05
Day 29	-0.19	-0.02
Day 57	-0.23	-0.07
Day 85	-0.13	0.03
Day 113	-0.18	0.07
Day 141	-0.31	0.16
Day 169	-0.29	0.16

13. Secondary Outcome

Title	Change From Baseline in Waist-to-hip Ratio
Description	Waist-to-hip ratio was derived using waist circumference and hip circumference, which was measured at the greatest protrusion of the buttocks. Change from baseline in waist-to-hip ratio was analyzed on a log-scale fitting a repeated measures mixed model including treatment and visit as fixed effects and log of baseline as continuous covariate. Baseline is the last measurement prior to treatment administration. No methods for imputation of missing data were used. Values reported were back-transformed to original scale. A negative score in the change from baseline indicates improvement.
Time Frame	Baseline and days 14, 29, 57, 85, 113, 141 and 169

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.

Arm/Group Title	LMB763	Placebo
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.	Placebo was orally administered once daily for 24 weeks in addition to SoC.
Measure Participants	41	41
Day 14	-0.00	-0.00
Day 29	-0.00	0.00
Day 57	-0.00	0.00
Day 85	-0.00	0.01
Day 113	-0.00	0.01
Day 141	-0.00	0.02
Day 169	-0.00	-0.00

Adverse Events

Time Frame	Adverse events were reported from the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 197 days
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 28 days post treatment
Arm/Group Title	LMB763		Placebo		Total
Arm/Group Description	50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC.		Placebo was orally administered once daily for 24 weeks in addition to SoC.		Total
All Cause Mortality
	LMB763		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0%)		0/42 (0%)		0/83 (0%)
Serious Adverse Events
	LMB763		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/41 (4.9%)		2/42 (4.8%)		4/83 (4.8%)
Infections and infestations
Erysipelas	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Metabolism and nutrition disorders
Hyperglycaemia	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Hypervolaemia	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Renal and urinary disorders
Renal disorder	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Acute kidney injury	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Skin and subcutaneous tissue disorders
Dermatitis atopic	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Other (Not Including Serious) Adverse Events
	LMB763		Placebo		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/41 (68.3%)		23/42 (54.8%)		51/83 (61.4%)
Blood and lymphatic system disorders
Anaemia	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Iron deficiency anaemia	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Nephrogenic anaemia	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Cardiac disorders
Angina pectoris	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Bradycardia	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Endocrine disorders
Hypothyroidism	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Gastrointestinal disorders
Abdominal pain	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Abdominal pain upper	2/41 (4.9%)		1/42 (2.4%)		3/83 (3.6%)
Colitis	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Constipation	2/41 (4.9%)		1/42 (2.4%)		3/83 (3.6%)
Diarrhoea	2/41 (4.9%)		0/42 (0%)		2/83 (2.4%)
Dry mouth	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Flatulence	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Gastritis	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Gastrooesophageal reflux disease	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Hyperchlorhydria	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Vomiting	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
General disorders
Asthenia	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Fatigue	2/41 (4.9%)		0/42 (0%)		2/83 (2.4%)
Oedema peripheral	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Pain	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Infections and infestations
Abdominal wall abscess	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Acarodermatitis	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Adenoviral conjunctivitis	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Bronchitis	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Cystitis	0/41 (0%)		2/42 (4.8%)		2/83 (2.4%)
Erysipelas	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Gastroenteritis	2/41 (4.9%)		1/42 (2.4%)		3/83 (3.6%)
Influenza	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Nasopharyngitis	1/41 (2.4%)		2/42 (4.8%)		3/83 (3.6%)
Sinusitis	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Soft tissue infection	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Urinary tract infection	2/41 (4.9%)		1/42 (2.4%)		3/83 (3.6%)
Urinary tract infection bacterial	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Injury, poisoning and procedural complications
Arthropod bite	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Injury	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Postoperative wound complication	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Rib fracture	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Scratch	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Soft tissue injury	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Investigations
Aspartate aminotransferase increased	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Blood bicarbonate decreased	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Blood creatine phosphokinase increased	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Blood creatinine increased	4/41 (9.8%)		3/42 (7.1%)		7/83 (8.4%)
Blood fibrinogen increased	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Blood glucose increased	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Blood pressure increased	0/41 (0%)		2/42 (4.8%)		2/83 (2.4%)
Blood uric acid increased	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Glycosylated haemoglobin increased	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Serum ferritin decreased	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Ultrasound scan abnormal	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Urine albumin/creatinine ratio increased	0/41 (0%)		3/42 (7.1%)		3/83 (3.6%)
Metabolism and nutrition disorders
Diabetes mellitus	0/41 (0%)		2/42 (4.8%)		2/83 (2.4%)
Hyperglycaemia	3/41 (7.3%)		2/42 (4.8%)		5/83 (6%)
Hyperkalaemia	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Hypokalaemia	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Iron deficiency	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Back pain	3/41 (7.3%)		2/42 (4.8%)		5/83 (6%)
Myalgia	2/41 (4.9%)		0/42 (0%)		2/83 (2.4%)
Pain in extremity	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Nervous system disorders
Cerebral artery stenosis	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Headache	2/41 (4.9%)		2/42 (4.8%)		4/83 (4.8%)
Neuropathy peripheral	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Sciatica	1/41 (2.4%)		1/42 (2.4%)		2/83 (2.4%)
Somnolence	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Psychiatric disorders
Insomnia	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Renal and urinary disorders
Acute kidney injury	0/41 (0%)		1/42 (2.4%)		2/83 (2.4%)
Chronic kidney disease	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Dysuria	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Renal colic	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Reproductive system and breast disorders
Pruritus genital	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Chronic obstructive pulmonary disease	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Oropharyngeal pain	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Skin and subcutaneous tissue disorders
Dry skin	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Hyperhidrosis	0/41 (0%)		1/42 (2.4%)		1/83 (1.2%)
Pruritus	13/41 (31.7%)		6/42 (14.3%)		19/83 (22.9%)
Urticaria	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Vascular disorders
Hypertension	2/41 (4.9%)		2/42 (4.8%)		4/83 (4.8%)
Hypotension	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)
Peripheral arterial occlusive disease	1/41 (2.4%)		0/42 (0%)		1/83 (1.2%)

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.