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

Diabetic Nephropathy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03804879
• Other study ID #: CLMB763X2202
• Secondary ID: 2018-002491-40
• Status: Completed
• Phase: Phase 2
• Start date: December 17, 2018
• Est. completion date: May 3, 2021

Study information

• Verified date: August 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 83
• Est. completion date: May 3, 2021
• Est. primary completion date: May 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Nephropathies
• Diabetic Nephropathy
• Kidney Diseases

Intervention

Drug:
• Nidufexor
50 mg (two 25 mg) LMB763 capsules for oral administration

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)

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Czechia	Novartis Investigative Site	Praha
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Elsterwerda
Germany	Novartis Investigative Site	Essen	Nordrhine Westphalia
Jordan	Novartis Investigative Site	Amman
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Saida
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Kocaeli
Turkey	Novartis Investigative Site	Talas / Kayseri
United States	Novartis Investigative Site	Albany	New York
United States	Novartis Investigative Site	El Paso	Texas
United States	Novartis Investigative Site	Miami Lakes	Florida
United States	Novartis Investigative Site	Norman	Oklahoma
United States	Novartis Investigative Site	Sugar Land	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Czechia,  Germany,  Jordan,  Lebanon,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline and days 14, 29, 57, 85, 113, 141 and 169
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.	Baseline and day 169
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.	From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 197 days
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.	Baseline and days 14, 29, 57, 85, 113, 141 and 169
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.	pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14
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.	pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14
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.	pre-dose and 1, 2, 4 and 6 hours after LMB763 administration on Day 1 and Day 14
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.	Baseline and day 169
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.	Baseline and day 85
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.	Baseline and day 169
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.	Baseline and days 14, 29, 57, 85, 113, 141 and 169
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.	Baseline and days 14, 29, 57, 85, 113, 141 and 169
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.	Baseline and days 14, 29, 57, 85, 113, 141 and 169

External Links

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