Diabetic Glomerulosclerosis, Diabetic Kidney Disease, Diabetic Nephropathy
Conditions
Keywords
Chronic Kidney Disease, Diabetic Kidney Disease, End-Stage Renal Disease, Transforming Growth Factor beta 1 Monoclonal Antibody, Type 1 Diabetes, Type 2 Diabetes
Brief summary
The purpose of this study is to determine if LY2382770 is safe and effective at protecting kidney function in participants with kidney disease due to diabetes.
Detailed description
The primary objective is to determine if LY2382770, administered monthly for 1 year, is more effective than placebo at slowing the progression of diabetic kidney disease in participants treated with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB).
Interventions
DRUGLY2382770
Subcutaneous injection given monthly for 12 months
DRUGPlacebo
Subcutaneous injection given monthly for 12 months
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Participants with chronic kidney disease presumed due to diabetes Type 1 or Type 2 * Participants with certain levels of kidney function - serum creatinine (SCr) 1.3 to 3.3 mg/dl (115 to 291 micromol/L) inclusive for women and 1.5 to 3.5 mg/dl (132 to 309 micromol/L) inclusive for men, or an estimated glomerular filtration rate (eGFR) 20 to 60 mL/min/1.73 m² * Participants with protein in the urine - 24-hour urine protein/creatinine ratio (PCR) greater than or equal to 800 mg/g (greater than or equal to 91 mg/mmol). * Participants must be on a stable and acceptable dose of an ACE (angiotensin-converting enzyme) inhibitor or an ARB (angiotensin II receptor blocker), or not able to tolerate these medications. Main
Exclusion criteria
* Female participants who can become pregnant, are pregnant or breastfeeding * Participants who have any of the following medical conditions (the site research staff will discuss these criteria and determine a participant's ability to participate) * Chronic inflammatory or autoimmune diseases * Chronic Kidney Disease from causes other than diabetes * An organ transplant * Too high a blood pressure * Viral Hepatitis B or C liver infection, liver cirrhosis, or significant liver disease * Recent gastrointestinal bleeding * Acute kidney injury within the 3 months before screening * Major surgery within 3 months before screening or plan to have it during the study period * HIV infection- the virus that causes AIDS * Heart disease that is not considered stable * Cancer that is too recent or other condition which poses too high a risk for developing cancer * Required to take drugs that change the immune system
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Log Transformed (In) Serum Creatinine From Baseline to 12 Month Endpoint | Baseline, 12 months | Analysis of covariance (ANCOVA) model was used with treatment, visit, and treatment-by-visit interaction as fixed effects, subject as random effect, baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) log transformed (ln) as covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Log Transformed (ln) Urine Protein/Creatinine Ratio From Baseline to 12 Month Endpoint | Baseline, 12 months | Analysis of covariance (ANCOVA) model was used with treatment, visit, and treatment-by-visit interaction as fixed effects, subject as random effect, baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) log transformed (ln) as covariates. |
| Population Pharmacokinetics (PK) - Model-Estimated Area Under the Concentration -Time Curve (AUC ) Over a Dosing Interval | Baseline through 12 months (samples collected pre and/or postdose at monthly intervals) | — |
| Log Transformed (ln) Serum Creatinine Slope of Change From Baseline Through 12 Months | Baseline through 12 months | Analysis of covariance (ANCOVA) model was used with treatment as fixed effects and baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) log transformed (ln) as covariates. |
| Estimated Glomerular Filtration Rate (eGFR) Slope of Change From Baseline Through 12 Months | Baseline through 12 months | Analysis of covariance (ANCOVA) model was used with treatment as fixed effects, baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) ) log transformed (ln) as covariates. |
Countries
Australia, Czechia, France, Hungary, Israel, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo given subcutaneous (SC) injection monthly for 12 months | 103 |
| 2 mg LY2382770 2 milligrams (mg) LY2382770 given (SC) injection monthly for 12 months | 105 |
| 10 mg LY2382770 10 mg LY2382770 given SC injection monthly for 12 months | 103 |
| 50 mg LY2382770 50 mg LY2382770 given SC injection monthly for 12 months | 105 |
| Total | 416 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 | 2 | 6 |
| Overall Study | Clinical Endpoint (ESRD) | 7 | 4 | 2 | 5 |
| Overall Study | Death | 4 | 5 | 3 | 4 |
| Overall Study | Physician Decision | 2 | 2 | 3 | 3 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Sponsor Decision | 15 | 21 | 20 | 15 |
| Overall Study | Withdrawal by Subject | 9 | 7 | 7 | 8 |
Baseline characteristics
| Characteristic | 2 mg LY2382770 | 10 mg LY2382770 | 50 mg LY2382770 | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.8 years STANDARD_DEVIATION 9.2 | 60.5 years STANDARD_DEVIATION 9.05 | 62.9 years STANDARD_DEVIATION 10.86 | 62.7 years STANDARD_DEVIATION 11.31 | 62.2 years STANDARD_DEVIATION 10.16 |
| Estimated Glomerular Filtration Rate (eGFR) | 35.705 milliliter/minute/1.73 meter squared STANDARD_DEVIATION 11.7226 | 36.358 milliliter/minute/1.73 meter squared STANDARD_DEVIATION 12.5154 | 35.945 milliliter/minute/1.73 meter squared STANDARD_DEVIATION 12.0852 | 33.835 milliliter/minute/1.73 meter squared STANDARD_DEVIATION 11.0568 | 35.464 milliliter/minute/1.73 meter squared STANDARD_DEVIATION 11.8539 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 11 Participants | 15 Participants | 8 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 53 Participants | 45 Participants | 55 Participants | 211 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 36 Participants | 39 Participants | 45 Participants | 40 Participants | 160 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 2 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 9 Participants | 7 Participants | 14 Participants | 39 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 6 Participants | 4 Participants | 17 Participants |
| Race (NIH/OMB) White | 90 Participants | 84 Participants | 90 Participants | 83 Participants | 347 Participants |
| Region of Enrollment Australia | 10 Participants | 10 Participants | 10 Participants | 10 Participants | 40 Participants |
| Region of Enrollment Czechia | 9 Participants | 10 Participants | 12 Participants | 14 Participants | 45 Participants |
| Region of Enrollment France | 9 Participants | 7 Participants | 8 Participants | 8 Participants | 32 Participants |
| Region of Enrollment Hungary | 16 Participants | 15 Participants | 15 Participants | 11 Participants | 57 Participants |
| Region of Enrollment Israel | 21 Participants | 21 Participants | 20 Participants | 20 Participants | 82 Participants |
| Region of Enrollment Puerto Rico | 5 Participants | 2 Participants | 5 Participants | 3 Participants | 15 Participants |
| Region of Enrollment United States | 35 Participants | 38 Participants | 36 Participants | 37 Participants | 146 Participants |
| Serum Creatinine | 2.127 milligram/deciliter (mg/dl) STANDARD_DEVIATION 0.5824 | 2.091 milligram/deciliter (mg/dl) STANDARD_DEVIATION 0.6538 | 2.132 milligram/deciliter (mg/dl) STANDARD_DEVIATION 0.6289 | 2.209 milligram/deciliter (mg/dl) STANDARD_DEVIATION 0.5917 | 2.140 milligram/deciliter (mg/dl) STANDARD_DEVIATION 0.6141 |
| Sex: Female, Male Female | 21 Participants | 29 Participants | 19 Participants | 27 Participants | 96 Participants |
| Sex: Female, Male Male | 84 Participants | 74 Participants | 86 Participants | 76 Participants | 320 Participants |
| Urine Protein/Creatinine Ratio | 3.266 gram/gram STANDARD_DEVIATION 2.5723 | 3.301 gram/gram STANDARD_DEVIATION 2.451 | 3.354 gram/gram STANDARD_DEVIATION 2.5457 | 3.123 gram/gram STANDARD_DEVIATION 2.518 | 3.262 gram/gram STANDARD_DEVIATION 2.5148 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 57 / 103 | 67 / 105 | 62 / 103 | 62 / 105 |
| serious Total, serious adverse events | 39 / 103 | 44 / 105 | 37 / 103 | 41 / 105 |
Outcome results
Primary
Change in Log Transformed (In) Serum Creatinine From Baseline to 12 Month Endpoint
Analysis of covariance (ANCOVA) model was used with treatment, visit, and treatment-by-visit interaction as fixed effects, subject as random effect, baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) log transformed (ln) as covariates.
Time frame: Baseline, 12 months
Population: All randomized participants who received at least 1 dose of drug and had evaluable baseline and post baseline serum creatinine values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Log Transformed (In) Serum Creatinine From Baseline to 12 Month Endpoint | 0.13 ln milligrams per deciliter [ln(mg/dL)] | Standard Error 0.019 |
| 2 mg LY2382770 | Change in Log Transformed (In) Serum Creatinine From Baseline to 12 Month Endpoint | 0.18 ln milligrams per deciliter [ln(mg/dL)] | Standard Error 0.019 |
| 10 mg LY2382770 | Change in Log Transformed (In) Serum Creatinine From Baseline to 12 Month Endpoint | 0.17 ln milligrams per deciliter [ln(mg/dL)] | Standard Error 0.019 |
| 50 mg LY2382770 | Change in Log Transformed (In) Serum Creatinine From Baseline to 12 Month Endpoint | 0.17 ln milligrams per deciliter [ln(mg/dL)] | Standard Error 0.02 |
Secondary
Change in Log Transformed (ln) Urine Protein/Creatinine Ratio From Baseline to 12 Month Endpoint
Analysis of covariance (ANCOVA) model was used with treatment, visit, and treatment-by-visit interaction as fixed effects, subject as random effect, baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) log transformed (ln) as covariates.
Time frame: Baseline, 12 months
Population: All randomized participants who received at least 1 dose of drug and had evaluable urine protein and creatinine ratio values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Log Transformed (ln) Urine Protein/Creatinine Ratio From Baseline to 12 Month Endpoint | 0.06 ln grams/grams [ln( g/g)] | Standard Error 0.076 |
| 2 mg LY2382770 | Change in Log Transformed (ln) Urine Protein/Creatinine Ratio From Baseline to 12 Month Endpoint | 0.05 ln grams/grams [ln( g/g)] | Standard Error 0.072 |
| 10 mg LY2382770 | Change in Log Transformed (ln) Urine Protein/Creatinine Ratio From Baseline to 12 Month Endpoint | 0.05 ln grams/grams [ln( g/g)] | Standard Error 0.073 |
| 50 mg LY2382770 | Change in Log Transformed (ln) Urine Protein/Creatinine Ratio From Baseline to 12 Month Endpoint | -0.01 ln grams/grams [ln( g/g)] | Standard Error 0.075 |
Secondary
Estimated Glomerular Filtration Rate (eGFR) Slope of Change From Baseline Through 12 Months
Analysis of covariance (ANCOVA) model was used with treatment as fixed effects, baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) ) log transformed (ln) as covariates.
Time frame: Baseline through 12 months
Population: All randomized participants who received at least 1 dose of drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Estimated Glomerular Filtration Rate (eGFR) Slope of Change From Baseline Through 12 Months | -0.3727 mL/min/1.73 m²/month | Standard Error 0.08599 |
| 2 mg LY2382770 | Estimated Glomerular Filtration Rate (eGFR) Slope of Change From Baseline Through 12 Months | -0.3664 mL/min/1.73 m²/month | Standard Error 0.08742 |
| 10 mg LY2382770 | Estimated Glomerular Filtration Rate (eGFR) Slope of Change From Baseline Through 12 Months | -0.5554 mL/min/1.73 m²/month | Standard Error 0.08512 |
| 50 mg LY2382770 | Estimated Glomerular Filtration Rate (eGFR) Slope of Change From Baseline Through 12 Months | -0.3980 mL/min/1.73 m²/month | Standard Error 0.08683 |
Secondary
Log Transformed (ln) Serum Creatinine Slope of Change From Baseline Through 12 Months
Analysis of covariance (ANCOVA) model was used with treatment as fixed effects and baseline Serum Creatinine log transformed (ln) and first morning urine protein to creatinine ratio (PCR) log transformed (ln) as covariates.
Time frame: Baseline through 12 months
Population: All randomized participants who received at least 1 dose of drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Log Transformed (ln) Serum Creatinine Slope of Change From Baseline Through 12 Months | 0.01605 ln milligrams per deciliter(mg/dL)/month | Standard Error 0.002685 |
| 2 mg LY2382770 | Log Transformed (ln) Serum Creatinine Slope of Change From Baseline Through 12 Months | 0.01408 ln milligrams per deciliter(mg/dL)/month | Standard Error 0.002731 |
| 10 mg LY2382770 | Log Transformed (ln) Serum Creatinine Slope of Change From Baseline Through 12 Months | 0.01716 ln milligrams per deciliter(mg/dL)/month | Standard Error 0.002658 |
| 50 mg LY2382770 | Log Transformed (ln) Serum Creatinine Slope of Change From Baseline Through 12 Months | 0.01337 ln milligrams per deciliter(mg/dL)/month | Standard Error 0.002712 |
Secondary
Population Pharmacokinetics (PK) - Model-Estimated Area Under the Concentration -Time Curve (AUC ) Over a Dosing Interval
Time frame: Baseline through 12 months (samples collected pre and/or postdose at monthly intervals)
Population: All randomized participants who received at least 1 dose of drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2 mg LY2382770 | Population Pharmacokinetics (PK) - Model-Estimated Area Under the Concentration -Time Curve (AUC ) Over a Dosing Interval | 54.4 microgram*hour per milliliter(µg•hr/mL) | Geometric Coefficient of Variation 49 |
| 10 mg LY2382770 | Population Pharmacokinetics (PK) - Model-Estimated Area Under the Concentration -Time Curve (AUC ) Over a Dosing Interval | 197 microgram*hour per milliliter(µg•hr/mL) | Geometric Coefficient of Variation 45 |
| 50 mg LY2382770 | Population Pharmacokinetics (PK) - Model-Estimated Area Under the Concentration -Time Curve (AUC ) Over a Dosing Interval | 957 microgram*hour per milliliter(µg•hr/mL) | Geometric Coefficient of Variation 44 |