Diabetic Nephropathy
Conditions
Keywords
diabetes
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.
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.
Interventions
DRUGNidufexor
50 mg (two 25 mg) LMB763 capsules for oral administration
OTHERPlacebo
Placebo capsules for oral administration
DRUGStandard of Care (SoC)
Optimal tolerated doses of angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Argentina, Czechia, Germany, Jordan, Lebanon, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants were recruited from 18 sites in 7 countries.
Pre-assignment details
Participants underwent a Screening period of up to 30 days which included screening and baseline assessments.
Participants by arm
| Arm | Count |
|---|---|
| LMB763 50 mg LMB763 (two LMB763 25 mg capsules) were orally administered once daily for 24 weeks in addition to SoC. | 41 |
| Placebo Placebo was orally administered once daily for 24 weeks in addition to SoC. | 42 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Study Terminated By Sponsor | 10 | 12 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | LMB763 |
|---|---|---|---|
| Age, Continuous | 61.6 Years STANDARD_DEVIATION 8.36 | 61.2 Years STANDARD_DEVIATION 8.61 | 60.8 Years STANDARD_DEVIATION 8.95 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 82 Participants | 41 Participants |
| Sex: Female, Male Female | 10 Participants | 23 Participants | 13 Participants |
| Sex: Female, Male Male | 32 Participants | 60 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 42 | 0 / 83 |
| other Total, other adverse events | 28 / 41 | 23 / 42 | 51 / 83 |
| serious Total, serious adverse events | 2 / 41 | 2 / 42 | 4 / 83 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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
Population: All randomized participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LMB763 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 29 Participants |
| LMB763 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 25 Participants |
Primary
Ratio to Baseline in 24 Hour Urinary Albumin at Week 24 (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.
Time frame: Baseline and day 169
Population: Pharmacodynamics (PD) analysis set. Only participants with a value at both baseline and at Day 169 were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LMB763 | Ratio to Baseline in 24 Hour Urinary Albumin at Week 24 (Day 169) | 0.58 Ratio to baseline |
| Placebo | Ratio to Baseline in 24 Hour Urinary Albumin at Week 24 (Day 169) | 0.91 Ratio to baseline |
Primary
Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR)
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
Population: All randomized participants. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 57 | 0.85 Ratio to baseline |
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 113 | 0.87 Ratio to baseline |
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 29 | 0.83 Ratio to baseline |
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 141 | 0.84 Ratio to baseline |
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 85 | 0.84 Ratio to baseline |
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 169 | 0.74 Ratio to baseline |
| LMB763 | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 14 | 0.90 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 169 | 0.92 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 14 | 1.06 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 29 | 1.00 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 57 | 1.05 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 85 | 1.07 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 113 | 1.07 Ratio to baseline |
| Placebo | Ratio to Baseline in Urinary Albumin to Creatinine Ratio (UACR) | Day 141 | 1.15 Ratio to baseline |
Secondary
Area Under the Blood Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of LMB763
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
Population: Pharmacokinetics (PK) analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LMB763 | Area Under the Blood Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of LMB763 | Day 1 | 3710 Hour*nanogram/milliliter | Standard Deviation 2510 |
| LMB763 | Area Under the Blood Concentration-time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) of LMB763 | Day 14 | 4850 Hour*nanogram/milliliter | Standard Deviation 2910 |
Secondary
Change From Baseline in Waist-to-hip Ratio
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
Population: Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 14 | -0.00 Ratio |
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 113 | -0.00 Ratio |
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 57 | -0.00 Ratio |
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 141 | -0.00 Ratio |
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 85 | -0.00 Ratio |
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 169 | -0.00 Ratio |
| LMB763 | Change From Baseline in Waist-to-hip Ratio | Day 29 | -0.00 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 169 | -0.00 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 29 | 0.00 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 57 | 0.00 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 14 | -0.00 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 85 | 0.01 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 113 | 0.01 Ratio |
| Placebo | Change From Baseline in Waist-to-hip Ratio | Day 141 | 0.02 Ratio |
Secondary
Maximum Peak Observed Concentration (Cmax) of LMB763
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
Population: Pharmacokinetics (PK) analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LMB763 | Maximum Peak Observed Concentration (Cmax) of LMB763 | Day 1 | 1090 Nanogram/milliliter | Standard Deviation 665 |
| LMB763 | Maximum Peak Observed Concentration (Cmax) of LMB763 | Day 14 | 1300 Nanogram/milliliter | Standard Deviation 691 |
Secondary
Percent Change From Baseline in Body Mass Index (BMI)
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
Population: Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 29 | -0.19 Percent change |
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 113 | -0.18 Percent change |
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 85 | -0.13 Percent change |
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 141 | -0.31 Percent change |
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 57 | -0.23 Percent change |
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 169 | -0.29 Percent change |
| LMB763 | Percent Change From Baseline in Body Mass Index (BMI) | Day 14 | -0.01 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 169 | 0.16 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 57 | -0.07 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 14 | -0.05 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 29 | -0.02 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 85 | 0.03 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 113 | 0.07 Percent change |
| Placebo | Percent Change From Baseline in Body Mass Index (BMI) | Day 141 | 0.16 Percent change |
Secondary
Percent Change From Baseline in Weight
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
Population: Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LMB763 | Percent Change From Baseline in Weight | Day 113 | -0.51 Percent change |
| LMB763 | Percent Change From Baseline in Weight | Day 14 | -0.08 Percent change |
| LMB763 | Percent Change From Baseline in Weight | Day 29 | -0.57 Percent change |
| LMB763 | Percent Change From Baseline in Weight | Day 57 | -0.69 Percent change |
| LMB763 | Percent Change From Baseline in Weight | Day 85 | -0.41 Percent change |
| LMB763 | Percent Change From Baseline in Weight | Day 141 | -0.80 Percent change |
| LMB763 | Percent Change From Baseline in Weight | Day 169 | -0.61 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 141 | 0.43 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 85 | 0.08 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 14 | -0.13 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 113 | 0.21 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 29 | -0.03 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 169 | 0.55 Percent change |
| Placebo | Percent Change From Baseline in Weight | Day 57 | -0.24 Percent change |
Secondary
Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR)
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
Population: Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 169 | 0.93 Ratio |
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 85 | 0.97 Ratio |
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 14 | 0.95 Ratio |
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 29 | 0.94 Ratio |
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 113 | 0.96 Ratio |
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 141 | 0.98 Ratio |
| LMB763 | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 57 | 0.98 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 113 | 0.94 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 57 | 0.96 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 29 | 0.94 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 85 | 0.94 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 169 | 0.93 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 141 | 0.93 Ratio |
| Placebo | Ratio to Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 14 | 0.96 Ratio |
Secondary
Ratio to Baseline in Free Water Clearance
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
Population: Pharmacodynamics (PD) analysis set. Only participants with a value at both baseline and at Day 169 were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LMB763 | Ratio to Baseline in Free Water Clearance | 0.97 Ratio |
| Placebo | Ratio to Baseline in Free Water Clearance | 0.97 Ratio |
Secondary
Ratio to Baseline in Lipoprotein A at 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.
Time frame: Baseline and day 169
Population: Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LMB763 | Ratio to Baseline in Lipoprotein A at Day 169 | 0.75 Ratio to baseline |
| Placebo | Ratio to Baseline in Lipoprotein A at Day 169 | 0.89 Ratio to baseline |
Secondary
Ratio to Baseline in Lipoprotein A at 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.
Time frame: Baseline and day 85
Population: Pharmacodynamics (PD) analysis set. At each time point, only participants with a value at both baseline and that time point were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LMB763 | Ratio to Baseline in Lipoprotein A at Day 85 | 0.72 Ratio |
| Placebo | Ratio to Baseline in Lipoprotein A at Day 85 | 0.95 Ratio |
Secondary
Time to Reach Maximum Blood Concentrations (Tmax) of LMB763
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
Population: Pharmacokinetics (PK) analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LMB763 | Time to Reach Maximum Blood Concentrations (Tmax) of LMB763 | Day 1 | 3.25 Hour |
| LMB763 | Time to Reach Maximum Blood Concentrations (Tmax) of LMB763 | Day 14 | 2 Hour |