Diabetic Kidney Disease
Conditions
Brief summary
This is a dose ranging study to evaluate the safety and efficacy of baricitinib in the treatment of participants with mild to moderate diabetic kidney disease.
Interventions
DRUGBaricitinib
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Incyte Corporation
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with Type 2 diabetes treated with at least one antihyperglycemic medicine for 12 months * Have diabetic kidney disease and receiving one of two specific medicines used to treat high blood pressure or diabetic kidney disease for at least 3 months * Estimated Glomerular Filtration Rate (eGFR) of 25 to 70 milliliter per minute per 1.73 square meter (mL/min/1.73 m²) (as determined by the Chronic Kidney Disease Epidemiology Collaboration equation) and a urinary albumin/creatinine ratio (UACR) \>300 milligram per gram (mg/g) and \<5000 mg/g
Exclusion criteria
* Too high blood pressure when you enter the study * Some specific medicines used to treat high blood pressure or diabetic kidney disease * Frequent high blood glucose levels * Renal transplant or past history of dialysis * Nonsteroidal anti-inflammatory drugs (NSAIDs) * Had a special X-ray in the past 30 days which involved also receiving an injection of dye into the vein * Major surgery within 8 weeks of study entry or will require major surgery during the study * Some types of vaccination * Shingles or currently have symptoms of a cold sore * Serious viral, bacterial, fungal, or parasitic infection, or a urinary infection, Tuberculosis (TB) * Human immunodeficiency virus (HIV) infection- the virus that causes Acquired immunodeficiency syndrome (AIDS) * Have or had some blood disorders, enlarged lymph glands or spleen, or some cancers. * Serious circulatory, breathing, liver, stomach or bowel problems, neurological or psychiatric disorders * Heart attack or heart failure, or a stroke * Other serious disorders or illnesses * Electrocardiogram (ECG) heart trace abnormalities * Alcohol or illegal drug abuse * Donated more than 500 mL of blood in the last 30 days (no blood donations allowed during the study) * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24 | Baseline, Week 24 | UACR is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine. The least squares mean (LS mean) are from mixed model repeated measures (MMRM) analyses which include treatment, baseline estimated Glomerular Filtration Rate (eGFR) group (higher: 50 to 70 mL/min/1.73m² and lower: 25 to \<50 mL/min/1.73m²), visit, treatment-by-visit interaction, baseline UACR, and baseline UACR-by-visit interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urinary Monocyte Chemotactic Protein 1 (MCP-1)/Creatinine Ratio | Baseline, Week 24 | — |
| Change From Baseline in Creatinine Clearance at Week 24 | Baseline, Week 24 | Creatinine clearance is the amount of creatinine cleared from kidney within 24 hours. The LS mean was from MMRM analyses which included treatment, baseline eGRF group, visit, treatment-by-visit interaction, baseline Creatinine Clearance, and baseline Creatinine Clearance-by-visit interaction. |
| Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Baseline, Week 24 | EQ-5D-5L is a 2-part measurement. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using the United Kingdom (UK) algorithm, with scores ranging from -0.594 to 1, and the United States (US) algorithm, with scores ranging from -0.109 to 1. A higher score indicates better health state. The second part is assessed using a visual analog scale (VAS) that ranged from 0 to 100mm, where 0 is the worst health you can imagine and 100 is the best health you can imagine. The LS means are analyzed using an analysis of covariance (ANCOVA) model with treatment, baseline eGFR group, and baseline VAS score or baseline health state index score as covariates. |
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady State (AUC,ss) | Weeks 2 and 4 (1-2 hours postdose), 8 (3-6 hours postdose), 12 (in fasted state), 16 and 20 (6-9 hours postdose), 24 (in fasted state) | Evaluable pharmacokinetic concentrations from the 2-week, 4-week, 8-week, 12-week, 16-week, 20-week and 24-week time points were combined and utilized in a population approach to determine the population mean estimate and standard deviation at steady-state. |
Countries
Japan, Mexico, Puerto Rico, United States
Participant flow
Recruitment details
The study included a 24-week treatment period and a 4- to 8-week washout period where study drug was discontinued. Time to loss-of-treatment benefit (defined as a failure to maintain a 30% decrease in UACR from baseline) was evaluated at Week 28. Participants who maintained treatment benefit were followed for an additional 4 weeks.
Pre-assignment details
Participants in each baricitinib dose group were classified by their baseline estimated glomerular filtration rate (eGFR) into higher (50 to 70 milliliter \[mL\]/minute \[min\]/1.73 meters squared \[m²\]) and lower (25 to \<50 mL/min/1.73 m²) eGFR strata. Participants in the lower strata had their dose adjusted to a lower dose.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo administered PO QD. | 27 |
| Baricitinib 0.75/0.5 mg QD Baricitinib 0.75 mg or 0.5 mg administered PO QD. | 25 |
| Baricitinib 0.75 mg/0.5 mg BID Baricitinib 0.75 mg or 0.5 mg administered PO BID. | 26 |
| Baricitinib 1.5 mg/1 mg QD Baricitinib 1.5 mg or 1 mg administered PO QD. | 26 |
| Baricitinib 4 mg/2.75 mg Baricitinib 4 mg or 2.75 administered PO QD. | 25 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Treatment Period (Weeks 1-24) | Adverse Event | 0 | 3 | 0 | 1 | 1 |
| Treatment Period (Weeks 1-24) | Inappropriately Enrolled | 0 | 0 | 1 | 0 | 0 |
| Treatment Period (Weeks 1-24) | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 |
| Treatment Period (Weeks 1-24) | Withdrawal by Subject | 0 | 0 | 0 | 1 | 1 |
| Washout Period 1 (Weeks 25-28) | Adverse Event | 0 | 4 | 0 | 1 | 2 |
| Washout Period 1 (Weeks 25-28) | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Washout Period 1 (Weeks 25-28) | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Washout Period 1 (Weeks 25-28) | Protocol Violation | 1 | 0 | 0 | 1 | 0 |
| Washout Period 1 (Weeks 25-28) | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 |
| Washout Period 2 (Weeks 29-32) | Adverse Event | 0 | 0 | 0 | 0 | 3 |
| Washout Period 2 (Weeks 29-32) | Physician Decision | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Baricitinib 0.75/0.5 mg QD | Baricitinib 0.75 mg/0.5 mg BID | Placebo | Baricitinib 1.5 mg/1 mg QD | Baricitinib 4 mg/2.75 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 63 Years STANDARD_DEVIATION 9.1 | 61 Years STANDARD_DEVIATION 10 | 64 Years STANDARD_DEVIATION 8.3 | 64 Years STANDARD_DEVIATION 9 | 61 Years STANDARD_DEVIATION 10.4 | 63 Years STANDARD_DEVIATION 7.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants | 4 Participants | 6 Participants | 4 Participants | 7 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 104 Participants | 21 Participants | 20 Participants | 23 Participants | 19 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 60 Participants | 12 Participants | 12 Participants | 14 Participants | 11 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 7 Participants | 3 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 43 Participants | 4 Participants | 9 Participants | 8 Participants | 13 Participants | 9 Participants |
| Region of Enrollment Japan | 52 Participants | 10 Participants | 10 Participants | 11 Participants | 10 Participants | 11 Participants |
| Region of Enrollment Mexico | 8 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants |
| Region of Enrollment Puerto Rico | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 68 Participants | 13 Participants | 14 Participants | 14 Participants | 14 Participants | 13 Participants |
| Sex: Female, Male Female | 35 Participants | 8 Participants | 5 Participants | 7 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 94 Participants | 17 Participants | 21 Participants | 20 Participants | 21 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 27 | 18 / 25 | 17 / 26 | 19 / 26 | 23 / 25 | 5 / 27 | 4 / 21 | 4 / 26 | 7 / 24 | 8 / 23 | 1 / 6 | 2 / 6 | 1 / 8 | 0 / 6 | 3 / 12 |
| serious Total, serious adverse events | 2 / 27 | 0 / 25 | 2 / 26 | 2 / 26 | 6 / 25 | 0 / 27 | 0 / 21 | 0 / 26 | 0 / 24 | 0 / 23 | 0 / 6 | 0 / 6 | 1 / 8 | 0 / 6 | 0 / 12 |
Outcome results
Primary
Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24
UACR is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine. The least squares mean (LS mean) are from mixed model repeated measures (MMRM) analyses which include treatment, baseline estimated Glomerular Filtration Rate (eGFR) group (higher: 50 to 70 mL/min/1.73m² and lower: 25 to \<50 mL/min/1.73m²), visit, treatment-by-visit interaction, baseline UACR, and baseline UACR-by-visit interaction.
Time frame: Baseline, Week 24
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24 | 1.12 milligram/gram (mg/g) | Standard Error 0.172 |
| Baricitinib 0.75 mg/0.5 mg QD | Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24 | 0.87 milligram/gram (mg/g) | Standard Error 0.155 |
| Baricitinib 0.75 mg/0.5 mg BID | Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24 | 0.85 milligram/gram (mg/g) | Standard Error 0.131 |
| Baricitinib 1.5 mg/1 mg | Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24 | 0.91 milligram/gram (mg/g) | Standard Error 0.143 |
| Baricitinib 4 mg/2.75 mg | Change From Baseline in Urinary Albumin/Creatinine Ratio (UACR) at Week 24 | 0.66 milligram/gram (mg/g) | Standard Error 0.111 |
Secondary
Change From Baseline in Creatinine Clearance at Week 24
Creatinine clearance is the amount of creatinine cleared from kidney within 24 hours. The LS mean was from MMRM analyses which included treatment, baseline eGRF group, visit, treatment-by-visit interaction, baseline Creatinine Clearance, and baseline Creatinine Clearance-by-visit interaction.
Time frame: Baseline, Week 24
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Creatinine Clearance at Week 24 | 0.93 milliliter/minute (mL/min) | Standard Error 0.07 |
| Baricitinib 0.75 mg/0.5 mg QD | Change From Baseline in Creatinine Clearance at Week 24 | 1.09 milliliter/minute (mL/min) | Standard Error 0.104 |
| Baricitinib 0.75 mg/0.5 mg BID | Change From Baseline in Creatinine Clearance at Week 24 | 0.86 milliliter/minute (mL/min) | Standard Error 0.069 |
| Baricitinib 1.5 mg/1 mg | Change From Baseline in Creatinine Clearance at Week 24 | 0.86 milliliter/minute (mL/min) | Standard Error 0.069 |
| Baricitinib 4 mg/2.75 mg | Change From Baseline in Creatinine Clearance at Week 24 | 0.080 milliliter/minute (mL/min) | Standard Error 0.066 |
Secondary
Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24
EQ-5D-5L is a 2-part measurement. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using the United Kingdom (UK) algorithm, with scores ranging from -0.594 to 1, and the United States (US) algorithm, with scores ranging from -0.109 to 1. A higher score indicates better health state. The second part is assessed using a visual analog scale (VAS) that ranged from 0 to 100mm, where 0 is the worst health you can imagine and 100 is the best health you can imagine. The LS means are analyzed using an analysis of covariance (ANCOVA) model with treatment, baseline eGFR group, and baseline VAS score or baseline health state index score as covariates.
Time frame: Baseline, Week 24
Population: All randomized participants who received at least one dose of study drug. Missing values were imputed with the last observation carried forward (LOCF) method.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (UK Algorithm) Week 24 | 0.00 Units on a Scale | Standard Error 0.03 |
| Placebo | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Self-Perceived Health Score | 2.62 Units on a Scale | Standard Error 2.94 |
| Placebo | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (US Algorithm) Week 24 | 0.00 Units on a Scale | Standard Error 0.02 |
| Baricitinib 0.75 mg/0.5 mg QD | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Self-Perceived Health Score | -1.97 Units on a Scale | Standard Error 3.02 |
| Baricitinib 0.75 mg/0.5 mg QD | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (US Algorithm) Week 24 | -0.03 Units on a Scale | Standard Error 0.02 |
| Baricitinib 0.75 mg/0.5 mg QD | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (UK Algorithm) Week 24 | -0.03 Units on a Scale | Standard Error 0.03 |
| Baricitinib 0.75 mg/0.5 mg BID | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (UK Algorithm) Week 24 | -0.01 Units on a Scale | Standard Error 0.03 |
| Baricitinib 0.75 mg/0.5 mg BID | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (US Algorithm) Week 24 | 0.00 Units on a Scale | Standard Error 0.02 |
| Baricitinib 0.75 mg/0.5 mg BID | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Self-Perceived Health Score | 0.28 Units on a Scale | Standard Error 2.95 |
| Baricitinib 1.5 mg/1 mg | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (UK Algorithm) Week 24 | -0.04 Units on a Scale | Standard Error 0.03 |
| Baricitinib 1.5 mg/1 mg | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (US Algorithm) Week 24 | -0.03 Units on a Scale | Standard Error 0.02 |
| Baricitinib 1.5 mg/1 mg | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Self-Perceived Health Score | -5.66 Units on a Scale | Standard Error 2.96 |
| Baricitinib 4 mg/2.75 mg | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Self-Perceived Health Score | 0.37 Units on a Scale | Standard Error 3.02 |
| Baricitinib 4 mg/2.75 mg | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (US Algorithm) Week 24 | 0.00 Units on a Scale | Standard Error 0.02 |
| Baricitinib 4 mg/2.75 mg | Change From Baseline in European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) at Week 24 | Index Score (UK Algorithm) Week 24 | 0.00 Units on a Scale | Standard Error 0.03 |
Secondary
Change From Baseline in Urinary Monocyte Chemotactic Protein 1 (MCP-1)/Creatinine Ratio
Time frame: Baseline, Week 24
Population: Zero participants analyzed. No data analyzed due to urinary MCP-1 and creatinine being measured on different urine samples from different time points and thus not able to correlate.
Secondary
Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady State (AUC,ss)
Evaluable pharmacokinetic concentrations from the 2-week, 4-week, 8-week, 12-week, 16-week, 20-week and 24-week time points were combined and utilized in a population approach to determine the population mean estimate and standard deviation at steady-state.
Time frame: Weeks 2 and 4 (1-2 hours postdose), 8 (3-6 hours postdose), 12 (in fasted state), 16 and 20 (6-9 hours postdose), 24 (in fasted state)
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady State (AUC,ss) | 198 nanomole*hour (nM*hr) | Standard Deviation 89.9 |
| Baricitinib 0.75 mg/0.5 mg QD | Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady State (AUC,ss) | 286 nanomole*hour (nM*hr) | Standard Deviation 92.4 |
| Baricitinib 0.75 mg/0.5 mg BID | Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady State (AUC,ss) | 388 nanomole*hour (nM*hr) | Standard Deviation 151 |
| Baricitinib 1.5 mg/1 mg | Pharmacokinetics (PK): Area Under the Concentration-Time Curve at Steady State (AUC,ss) | 1250 nanomole*hour (nM*hr) | Standard Deviation 577 |