Diabetic Nephropathy
Conditions
Brief summary
The purpose of this two-part study is to investigate the safety, tolerability and efficacy of LY3016859 after multiple intravenous (IV) dosing's in participants with diabetic nephropathy (DN). Part A will be dose escalation for safety and tolerability and Part B will evaluate Proteinuria.
Interventions
DRUGPlacebo
Administered IV
DRUGLY3016859
Administered IV
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
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Stable diabetic kidney disease (DKD) while taking Standard of Care medication (SOC), as defined by: * Estimated glomerular filtration rate (eGFR) less than (\<) 90 milliliter per minute per 1.73 square meter (ml/min/1.73m²) as determine utilizing the Modification of Diet in Renal Disease (MDRD) equation * Taking an angiotensin convertible enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) at a stable dose for greater than or equal to (≥) 2 months prior to randomization and agree to continue to take such throughout the duration of the study * Type 1 or Type 2 diabetes on a stable treatment regimen and adequately controlled in the opinion of the investigator * First morning protein-creatine ratio (PCR) at screening ≥400 milligrams per gram (mg/g) (Part B only) * Clinical chemistry labs within acceptable range for the participant population, as per investigator judgment * Men and women of non-childbearing potential as determined by medical history and physical examination * Non-vasectomized male participants must agree to use a medically accepted method of contraception with all sexual partners during the study and for 90 days following the final dosing. Medically accepted effective forms of contraception may include condoms with contraceptive foam or having partners use diaphragms with contraceptive jelly or cervical caps with contraceptive jelly * Female participants must be postmenopausal or surgically sterile to participate in this study. This is defined as females between age 45 to 75 years, inclusive, and either 12 months without a menstrual period \[no follicle stimulating hormone (FSH) test required\] or 6-12 months without a menstrual period and follicle stimulating hormone (FSH) greater than (\>) 40 international units per liter (IU/L) * Must weigh ≥50 kilograms (kg) at time of screening and dosing * Acceptable sitting blood pressure (BP) per the following American Heart Association (AHA) guidelines: * Normal: systolic blood pressure (SBP) \<120 millimeters of mercury (mmHg) and diastolic blood pressure (DBP) \<80 mmHg * Prehypertension: SBP 120-139 or DBP 80-89 * High Blood Pressure (Hypertension) Stage 1: SBP 140-159 mmHg or DBP 90-99 * Have given written informed consent prior to any study-specific procedures * Are reliable and willing to make themselves available for the duration of the study and are willing to follow site specific study procedures * Have venous access sufficient to allow blood sampling * Have laboratory values and other safety parameters that are, in the opinion of the investigator, acceptable fo participation for the study
Exclusion criteria
* Have a diagnosis of chronic kidney disease (CKD) other than DKD, (hypertensive nephrosclerosis superimposed on DKD is acceptable) * Have SBP \>160 mmHg or DBP \>100 mmHg o Individuals with Stage 1 BP elevation (SBP 140-159 mmHg or DBP 90-99 mmHg) on some occasions during study, may be acceptable, as long as only non-protein-lowering antihypertensives are adjusted to achieve target BP goals (\<140/90 mmHg) * Current use of (or within 2 weeks of enrollment), or projected need for a renin inhibitor or aldosterone antagonist, or a combination of Angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB) * Individuals in whom dialysis or transplantation is anticipated within 6 months of screening * Have a history of acute kidney injury within 3 months of screening * Are currently enrolled in, or discontinued within the last 60 days from, a clinical trial involving an investigational drug that has not received regulatory approval for any indication and/or have received treatment with biologic agents (such as monoclonal antibodies) within 3 months or 5 half-lives of the administered drug (whichever is longer) prior to dosing * Have previously completed or withdrawn from this study or any other study investigating LY3016859 * Have a diagnosis of Class III or IV congestive heart failure (as defined by the New York Heart Association) * Have an abnormality in the 12-lead Electrocardiogram (ECG) that, in the opinion of the investigator increases the risks associated with participating in the study. In addition, individuals with the following findings will be excluded: * Confirmed corrected QT (QTcF) interval \>450 milliseconds (msec) for men and \>470 msec for women * Irregular rhythms other than sinus arrhythmia or occasional, rare supraventricular ectopic beats * History of unexplained syncope * Family history of unexplained sudden death or sudden death due to long QT syndrome * T-wave configurations are not of sufficient quality for assessing QT interval, as determined by the investigator * Have evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies; have a history of cirrhosis or hepatitis C or are positive for hepatitis C antibody at the screening visit; are known to be hepatitis B surface antigen-positive or are positive for hepatitis B surface antigen at the screening visit * Are unwilling to discontinue use of Chinese herbs for at least 2 weeks prior to randomization and for the duration of their study participation * Are unwilling or unable to comply with the use of a data collection device to directly record data from the participant * Have donated blood of more than 500 milliliters (mL) within the last 60 days prior to screening * Have an average weekly alcohol intake that exceeds 21 units per week or are unwilling to stop alcohol intake within 48 hours of entry into study and for the duration of the study (1 unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits) * Individuals who, in the opinion of the investigator, show evidence of regular use of drugs of abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part B:Change From Baseline in Proteinuria | Baseline, 16 Weeks | Proteinuria is defined as the ratio of protein to creatinine. |
| Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | Baseline up to 32 Weeks | Treatment-emergent adverse events (TEAEs) are events which were not present at baseline or pre-existing conditions at baseline that worsened in severity following the start of treatment. A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Change From Baseline in Proteinuria Over Time | Baseline, 19 Weeks | Proteinuria is defined as the ratio of protein to creatinine. |
| Part B: Change From Baseline in Albuminuria Over Time | Baseline, 19 Weeks | Albuminuria is defined as the ratio of albumin to creatinine. |
Countries
Bulgaria, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Part A) Part A: Placebo administered by 60 minute Intravenous (IV) infusion at Week 1 and Week 4. | 3 |
| 10 mg LY3016859 (Part A) Part A: 10 milligram (mg) LY3016859 administered by 60 minute IV infusion at Week 1 and Week 4. | 4 |
| 100 mg LY3016859 (Part A) Part A:100 mg LY3016859 administered by 60 minute IV infusion at Week 1 and Week 4. | 4 |
| 750 mg LY3016859 (Part A) Part A: 750 mg LY3016859 administered by 60 minute IV infusion at Week 1 and Week 4. | 4 |
| Placebo (Part B) Part B: Placebo administered by 60 minute IV infusion at Weeks 1, 4, 7, 10 and 13. | 6 |
| 50 mg LY3016859 (Part B) Part B: 50 mg LY3016859 administered by 60 minute IV infusion at Weeks 1, 4, 7, 10 and 13. | 14 |
| 250 mg LY3016859 (Part B) Part B: 250 mg LY3016859 administered by 60 minute IV infusion at Weeks 1, 4, 7, 10 and 13. | 13 |
| 750 mg LY3016859 (Part B) Part B: 750 mg LY3016859 administered by 60 minute IV infusion at Weeks 1, 4, 7, 10 and 13. | 12 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo (Part A) | 10 mg LY3016859 (Part A) | 100 mg LY3016859 (Part A) | 750 mg LY3016859 (Part A) | Placebo (Part B) | 50 mg LY3016859 (Part B) | 250 mg LY3016859 (Part B) | 750 mg LY3016859 (Part B) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 10 | 57 years STANDARD_DEVIATION 7.2 | 56 years STANDARD_DEVIATION 6.1 | 62 years STANDARD_DEVIATION 11.6 | 55 years STANDARD_DEVIATION 5 | 63 years STANDARD_DEVIATION 8.3 | 55 years STANDARD_DEVIATION 12.7 | 59 years STANDARD_DEVIATION 9.5 | 58.5 years STANDARD_DEVIATION 9.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants | 5 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 10 Participants | 13 Participants | 7 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 6 Participants | 12 Participants | 13 Participants | 12 Participants | 58 Participants |
| Region of Enrollment Bulgaria | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 4 Participants | 0 Participants | 3 Participants | 18 Participants |
| Region of Enrollment United Kingdom | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Region of Enrollment United States | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 10 Participants | 13 Participants | 9 Participants | 37 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants | 7 Participants | 4 Participants | 6 Participants | 28 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 7 Participants | 9 Participants | 6 Participants | 32 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 6 | 0 / 14 | 0 / 13 | 0 / 12 |
| other Total, other adverse events | 1 / 3 | 3 / 4 | 4 / 4 | 2 / 4 | 6 / 6 | 13 / 14 | 13 / 13 | 11 / 12 |
| serious Total, serious adverse events | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 6 | 3 / 14 | 6 / 13 | 2 / 12 |
Outcome results
Primary
Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs
Treatment-emergent adverse events (TEAEs) are events which were not present at baseline or pre-existing conditions at baseline that worsened in severity following the start of treatment. A summary of other non-serious Adverse Events (AEs), and all Serious Adverse Events (SAE's), regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline up to 32 Weeks
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 1 Participants |
| 50 mg LY3016859 (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 3 Participants |
| 250 mg LY3016859 (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 4 Participants |
| 750 mg LY3016859 (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 2 Participants |
| Placebo (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 6 Participants |
| 50 mg LY3016859 (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 13 Participants |
| 250 mg LY3016859 (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 13 Participants |
| 750 mg LY3016859 (Part B) | Part A and Part B: Number of Participants With One or More Treatment Emergent Adverse Events (AEs) or Any Serious AEs | 11 Participants |
Primary
Part B:Change From Baseline in Proteinuria
Proteinuria is defined as the ratio of protein to creatinine.
Time frame: Baseline, 16 Weeks
Population: All randomized participants who received at least one dose of study drug in Part B with a baseline measurement and at least one post-baseline measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part B) | Part B:Change From Baseline in Proteinuria | 1.5 grams per 12 hour (g/12 hour) | Standard Deviation 2.04 |
| 50 mg LY3016859 (Part B) | Part B:Change From Baseline in Proteinuria | -0.4 grams per 12 hour (g/12 hour) | Standard Deviation 1.6 |
| 250 mg LY3016859 (Part B) | Part B:Change From Baseline in Proteinuria | 0.1 grams per 12 hour (g/12 hour) | Standard Deviation 1.21 |
| 750 mg LY3016859 (Part B) | Part B:Change From Baseline in Proteinuria | 0.7 grams per 12 hour (g/12 hour) | Standard Deviation 2.23 |
p-value: 0.0449t-test, 1 sided
p-value: 0.0808t-test, 1 sided
p-value: 0.2219t-test, 1 sided
Secondary
Part B: Change From Baseline in Albuminuria Over Time
Albuminuria is defined as the ratio of albumin to creatinine.
Time frame: Baseline, 19 Weeks
Population: All randomized participants who received at least one dose of study drug and were in Part B with a baseline measurement and at least one post-baseline measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part B) | Part B: Change From Baseline in Albuminuria Over Time | 8.6 mg/dl of albumin/ by mg/dl of creatinine | Standard Deviation 100.57 |
| 50 mg LY3016859 (Part B) | Part B: Change From Baseline in Albuminuria Over Time | -15.6 mg/dl of albumin/ by mg/dl of creatinine | Standard Deviation 64.27 |
| 250 mg LY3016859 (Part B) | Part B: Change From Baseline in Albuminuria Over Time | -8.1 mg/dl of albumin/ by mg/dl of creatinine | Standard Deviation 50.19 |
| 750 mg LY3016859 (Part B) | Part B: Change From Baseline in Albuminuria Over Time | 36.7 mg/dl of albumin/ by mg/dl of creatinine | Standard Deviation 93.49 |
Secondary
Part B: Change From Baseline in Proteinuria Over Time
Proteinuria is defined as the ratio of protein to creatinine.
Time frame: Baseline, 19 Weeks
Population: All randomized participants who received at least one dose of study drug and were in Part B with a baseline measurement and at least one post-baseline measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part B) | Part B: Change From Baseline in Proteinuria Over Time | 19.3 mg/dl of protein/ by mg/dl of creatinine | Standard Deviation 154.66 |
| 50 mg LY3016859 (Part B) | Part B: Change From Baseline in Proteinuria Over Time | -17.3 mg/dl of protein/ by mg/dl of creatinine | Standard Deviation 81.95 |
| 250 mg LY3016859 (Part B) | Part B: Change From Baseline in Proteinuria Over Time | -2.4 mg/dl of protein/ by mg/dl of creatinine | Standard Deviation 88.01 |
| 750 mg LY3016859 (Part B) | Part B: Change From Baseline in Proteinuria Over Time | 48.6 mg/dl of protein/ by mg/dl of creatinine | Standard Deviation 130.13 |