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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Diabetic Nephropathy

Intervention / Treatment
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* Drug: Nidufexor
* Other: Placebo
* Drug: Standard of Care (SoC)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and days 14, 29, 57, 85, 113, 141 and 169 | 
| 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. | Baseline and day 169 | 
| 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. | From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 197 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and days 14, 29, 57, 85, 113, 141 and 169 | 
| 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. | pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14 | 
| 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. | pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14 | 
| 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. | pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14 | 
| 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. | Baseline and day 169 | 
| 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. | Baseline and day 85 | 
| 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. | Baseline and day 169 | 
| 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. | Baseline and days 14, 29, 57, 85, 113, 141 and 169 | 
| 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. | Baseline and days 14, 29, 57, 85, 113, 141 and 169 | 
| 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. | Baseline and days 14, 29, 57, 85, 113, 141 and 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetes