Diabetic Kidney Disease
Conditions
Brief summary
The purpose of this study is to determine whether BMS-813160 will reduce the amount of protein loss in the urine of subjects with type 2 diabetes and diabetic kidney disease
Interventions
DRUGBMS-813160
DRUGPlacebo matching with BMS-813160
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: * Clinical diagnosis of type 2 diabetes mellitus with macroalbuminuria (UACR between 200 and 3500 mg/g) * Background angiotensin converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) therapy
Exclusion criteria
* Clinical diagnosis of type 1 diabetes * Unstable cardiovascular, metabolic, or other chronic disease status * Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m2 * High risk of infection or immune compromise * Clinically significant ECG conduction abnormalities * Drugs with significant potential to affect BMS-813160 exposure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Baseline, Weeks 2, 4, 8, 12, and 16 (Follow-up) | The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples. UACR was calculated as the geometric mean of two first-morning void urine UACR measurements with samples collected on two separate occasions within a 4-day period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Baseline up to Week 16 | 12-lead ECGs were performed before and 1 hour after dosing at Weeks 0, 2 and 4. ECGs were recorded after the participant has been supine for at least 5 minutes. The PR interval was defined as the beginning of the P wave to the beginning of the QRS complex, and represents the time taken by electrical impulse to travel from the sinus node through the atrioventricular (AV) node. The QRS complex represented the rapid depolarization of the right and left ventricles. The QT interval was defined as the time from the start of the Q wave to the end of the T wave, and represents the time taken for ventricular depolarization and repolarization. Participants were evaluated for abnormal ECG intervals. Criteria's for abnormality were PR \>200, QRS \>120, QT \>500, QTcF \>450, Change From Baseline \>30 milliseconds (msec). |
| Trough Observed Plasma Concentration (Ctrough) of BMS-813160 | Pre-dose at Week 2, 4, 8, 12 and 0.5, 1, 2, 4, and 6 hours post-dose at Week 12 | Ctrough is the minimum estimated plasma concentration at steady state. |
| Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | From the date of subject's written consent until 30 days post discontinuation of dosing, assessed up to 26 months | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability/incapacity, or a congenital anomaly, or a medically important event. |
| Renal Clearance (CLr) of BMS-813160 | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Week 12 | CLr was calculated by dividing the total amount excreted in the urine from 0 to 6 hours by the area under the plasma concentration-time curve from time zero extrapolated to infinite time. The renal function was classified based on estimated glomerular filtration rate as normal (\>=90 mL/min/1.73 m\^2), mildly impaired (60-89 mL/min/1.73 m\^2), moderately impaired stage 3A (45-59 mL/min/1.73 m\^2), and moderately impaired stage 3B (30-44 L/min/1.73 m\^2). |
| Dose-Response Relationship Using Change in Baseline Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment | Baseline, Weeks 2, 4, 8 and 12 | The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples. UACR was calculated as the geometric mean of two first-morning void urine UACR measurements with samples collected on two separate occasions within a 4-day period. The effect of BMS-813160 on urinary albumin excretion as measured by UACR values in participants with diabetic kidney disease after 12 weeks of treatment was assessed. The model included treatment group as a main effect, and the log of baseline UACR values, as well as baseline values of eGFR, blood pressure, blood glucose and lipid levels, as covariates. |
| Area Under The Plasma Concentration-Time Curve From Time Zero to 6 Hours Post-Dose [AUC(0-6 h)] | Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Week 12 | AUC(0-6 h) is the area under the plasma concentration-time curve from pre-dose (0 h) to 6 h post-dose. |
Countries
Canada, Denmark, France, United States
Participant flow
Pre-assignment details
319 were enrolled, 110 completed screening, rest 209 discontinued: (Main reason:did not meet study criteria). Of 110 screened, 98 entered Placebo Lead-in period of which 89 completed period, rest 9 discontinued (2 due to Admin. reason, 3 no longer met study criteria, 2 AEs and 2 were lost to follow-up.)1 was randomized but declined treatment
Participants by arm
| Arm | Count |
|---|---|
| BMS-813160 150 mg QD Participants received BMS-813160 150 mg, capsule, orally along with matching placebo in Ante Meridiem (AM) and 2 Placebo matching with BMS-813160, capsules, orally in Post Meridiem (PM) for 12 weeks. Participants were followed up for 4 weeks post treatment. | 29 |
| BMS-813160 300 mg BID Participants received 2 BMS-813160 150 mg capsules, orally, twice daily (2\*150 in AM and 2\*150 in PM) for 12 weeks. Participants were followed up for 4 weeks post treatment. | 30 |
| Placebo Participants received BMS-813160 matching placebo capsules, orally, twice daily in AM and PM for 12 weeks and were followed up for 4 weeks post treatment. | 29 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Treatment Period | Adverse Event | 2 | 1 | 2 |
| Treatment Period | Lost to Follow-up | 0 | 0 | 1 |
| Treatment Period | Subject no longer meets study criteria | 0 | 1 | 1 |
| Treatment Period | Subject request to discontinue treatment | 1 | 0 | 1 |
| Treatment Period | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | BMS-813160 150 mg QD | BMS-813160 300 mg BID | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 9.58 | 60.2 Years STANDARD_DEVIATION 8.31 | 60.6 Years STANDARD_DEVIATION 11.52 | 61.5 Years STANDARD_DEVIATION 9.9 |
| Age, Customized <65 years | 14 Participants | 17 Participants | 17 Participants | 48 Participants |
| Age, Customized >=65 years | 15 Participants | 13 Participants | 12 Participants | 40 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 27 Participants | 23 Participants | 21 Participants | 71 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 1 / 30 | 0 / 29 |
| other Total, other adverse events | 3 / 29 | 2 / 30 | 4 / 29 |
| serious Total, serious adverse events | 3 / 29 | 3 / 30 | 1 / 29 |
Outcome results
Primary
Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160
The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples. UACR was calculated as the geometric mean of two first-morning void urine UACR measurements with samples collected on two separate occasions within a 4-day period.
Time frame: Baseline, Weeks 2, 4, 8, 12, and 16 (Follow-up)
Population: The analysis was performed in all the participants who received any study drug. Here, 'n' signifies evaluable participants for specified categories in respective treatment arms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMS-813160 150 mg QD | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 2 | 5.78 Percent Change | Standard Deviation 48.994 |
| BMS-813160 150 mg QD | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 12 | 6.91 Percent Change | Standard Deviation 56.666 |
| BMS-813160 150 mg QD | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 8 | 19.49 Percent Change | Standard Deviation 65.381 |
| BMS-813160 150 mg QD | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 16 | 0.97 Percent Change | Standard Deviation 61.72 |
| BMS-813160 150 mg QD | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 4 | 18.43 Percent Change | Standard Deviation 62.661 |
| BMS-813160 300 mg BID | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 16 | 20.63 Percent Change | Standard Deviation 85.578 |
| BMS-813160 300 mg BID | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 2 | 3.79 Percent Change | Standard Deviation 62.795 |
| BMS-813160 300 mg BID | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 4 | 5.81 Percent Change | Standard Deviation 83.274 |
| BMS-813160 300 mg BID | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 8 | 9.87 Percent Change | Standard Deviation 56.557 |
| BMS-813160 300 mg BID | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 12 | 29.16 Percent Change | Standard Deviation 78.69 |
| Placebo | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 4 | 1.46 Percent Change | Standard Deviation 40.051 |
| Placebo | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 16 | 23.77 Percent Change | Standard Deviation 70.411 |
| Placebo | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 12 | 8.91 Percent Change | Standard Deviation 54.025 |
| Placebo | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 2 | 2.05 Percent Change | Standard Deviation 30.771 |
| Placebo | Percent Change From Baseline in Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment With BMS-813160 | Week 8 | 5.68 Percent Change | Standard Deviation 43.659 |
Secondary
Area Under The Plasma Concentration-Time Curve From Time Zero to 6 Hours Post-Dose [AUC(0-6 h)]
AUC(0-6 h) is the area under the plasma concentration-time curve from pre-dose (0 h) to 6 h post-dose.
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Week 12
Population: The analysis was planned to be performed in the Pharmacokinetic (PK) analysis set which included all participants who receive a dose of study drug and have adequate PK concentration-time data. Data was not collected for any participants due to termination of the study
Secondary
Dose-Response Relationship Using Change in Baseline Urinary Albumin-to-Creatinine Ratio (UACR) Across 12 Weeks of Treatment
The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples. UACR was calculated as the geometric mean of two first-morning void urine UACR measurements with samples collected on two separate occasions within a 4-day period. The effect of BMS-813160 on urinary albumin excretion as measured by UACR values in participants with diabetic kidney disease after 12 weeks of treatment was assessed. The model included treatment group as a main effect, and the log of baseline UACR values, as well as baseline values of eGFR, blood pressure, blood glucose and lipid levels, as covariates.
Time frame: Baseline, Weeks 2, 4, 8 and 12
Population: Data was not collected for any participants due to termination of the study
Secondary
Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval
12-lead ECGs were performed before and 1 hour after dosing at Weeks 0, 2 and 4. ECGs were recorded after the participant has been supine for at least 5 minutes. The PR interval was defined as the beginning of the P wave to the beginning of the QRS complex, and represents the time taken by electrical impulse to travel from the sinus node through the atrioventricular (AV) node. The QRS complex represented the rapid depolarization of the right and left ventricles. The QT interval was defined as the time from the start of the Q wave to the end of the T wave, and represents the time taken for ventricular depolarization and repolarization. Participants were evaluated for abnormal ECG intervals. Criteria's for abnormality were PR \>200, QRS \>120, QT \>500, QTcF \>450, Change From Baseline \>30 milliseconds (msec).
Time frame: Baseline up to Week 16
Population: The analysis was performed in all the participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BMS-813160 150 mg QD | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | PR >200 msec | 8 Participants |
| BMS-813160 150 mg QD | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QRS >120 msec | 3 Participants |
| BMS-813160 150 mg QD | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QT >500 msec | 0 Participants |
| BMS-813160 150 mg QD | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QTcF >450 msec | 7 Participants |
| BMS-813160 150 mg QD | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Change from baseline in QT >30 msec | 8 Participants |
| BMS-813160 150 mg QD | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Change from baseline in QTcF >30 msec | 4 Participants |
| BMS-813160 300 mg BID | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Change from baseline in QTcF >30 msec | 3 Participants |
| BMS-813160 300 mg BID | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | PR >200 msec | 8 Participants |
| BMS-813160 300 mg BID | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QTcF >450 msec | 5 Participants |
| BMS-813160 300 mg BID | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Change from baseline in QT >30 msec | 6 Participants |
| BMS-813160 300 mg BID | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QRS >120 msec | 3 Participants |
| BMS-813160 300 mg BID | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QT >500 msec | 1 Participants |
| Placebo | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QRS >120 msec | 3 Participants |
| Placebo | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QT >500 msec | 0 Participants |
| Placebo | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Change from baseline in QTcF >30 msec | 1 Participants |
| Placebo | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | QTcF >450 msec | 6 Participants |
| Placebo | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | PR >200 msec | 4 Participants |
| Placebo | Number of Participants With Out-of-Range Electrocardiogram (ECG) Interval | Change from baseline in QT >30 msec | 4 Participants |
Secondary
Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability/incapacity, or a congenital anomaly, or a medically important event.
Time frame: From the date of subject's written consent until 30 days post discontinuation of dosing, assessed up to 26 months
Population: The analysis was performed in all the participants who received any study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BMS-813160 150 mg QD | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | Death | 0 Participants |
| BMS-813160 150 mg QD | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | SAEs | 3 Participants |
| BMS-813160 150 mg QD | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | Other (Non-Serious) Adverse Events 5 % cut-off | 3 Participants |
| BMS-813160 300 mg BID | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | Death | 1 Participants |
| BMS-813160 300 mg BID | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | SAEs | 3 Participants |
| BMS-813160 300 mg BID | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | Other (Non-Serious) Adverse Events 5 % cut-off | 2 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | SAEs | 1 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | Other (Non-Serious) Adverse Events 5 % cut-off | 4 Participants |
| Placebo | Number of Participants With Serious Adverse Events (SAEs), Who Died and With Other (Not Including Serious) Adverse Events | Death | 0 Participants |
Secondary
Renal Clearance (CLr) of BMS-813160
CLr was calculated by dividing the total amount excreted in the urine from 0 to 6 hours by the area under the plasma concentration-time curve from time zero extrapolated to infinite time. The renal function was classified based on estimated glomerular filtration rate as normal (\>=90 mL/min/1.73 m\^2), mildly impaired (60-89 mL/min/1.73 m\^2), moderately impaired stage 3A (45-59 mL/min/1.73 m\^2), and moderately impaired stage 3B (30-44 L/min/1.73 m\^2).
Time frame: Pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose at Week 12
Population: The analysis was planned to be performed in the Pharmacokinetic (PK) analysis set which included all participants who receive a dose of study drug and have adequate PK concentration-time data.Data was not collected for any participants due to termination of the study
Secondary
Trough Observed Plasma Concentration (Ctrough) of BMS-813160
Ctrough is the minimum estimated plasma concentration at steady state.
Time frame: Pre-dose at Week 2, 4, 8, 12 and 0.5, 1, 2, 4, and 6 hours post-dose at Week 12
Population: The analysis was planned to be performed in the Pharmacokinetic (PK) analysis set which included all participants who receive a dose of study drug and have adequate PK concentration-time data. Data was not collected for any participants due to termination of the study