Type 2 Diabetes Mellitus
Conditions
Brief summary
The main purpose of the trial is to determine the effect of a study drug known as LY2409021 on blood pressure and pulse rate in participants with type 2 diabetes mellitus (T2DM) when compared to placebo. The study has two periods. Each participant will receive LY2409021 or placebo in each period. At least 4 weeks will pass between periods. The study will last about 23 weeks for each participant. Participants may remain on stable dose metformin, as prescribed by their personal physician.
Interventions
DRUGLY2409021
Administered orally
DRUGPlacebo
Administered orally
DRUGMetformin
Administered as background therapy.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have type 2 diabetes mellitus (according to the World Health Organization diagnostic criteria) and use diet and exercise alone or in combination with a stable dose of metformin ( \>/=1000 mg/day \[or \<1000 mg, if documented intolerance to 1000 mg or higher dosages\] immediate-release metformin or extended-release metformin for at least 2 months before screening). * Have glycated hemoglobin (HbA1c) values \>/=6.5% and \</=8.5%, as determined by the central laboratory at screening. * Have mean blood pressures \>90/60 millimeters of mercury (mm Hg) and \<140/90 mm Hg at screening. * If being treated for hypertension, are taking 3 or fewer antihypertensive medications and have been taking stable doses of the same medications for at least 1 month before screening. * Stable body weights (±5%) for \>/=3 months before screening. * Body mass indexes \>/=20 kilograms/meters squared (kg/m²) and \<40 kg/m². * In the investigator's opinion, are well motivated, capable, and willing to: * Reliably administer the oral study drug once daily; * Maintain a study diary; * Perform self-monitored blood glucose testing; and * Wear an ambulatory blood pressure monitoring device for at least 24 hours (on multiple occasions). * Are women not of child-bearing potential due to: * Surgical sterilization, hysterectomy, or bilateral oophorectomy (at least 6 weeks postsurgery) or tubal ligation (confirmed by medical history); or * Menopause. Women with an intact uterus are deemed menopausal if they have a cessation of menses for at least 1 year with follicle stimulating hormone \>40 milli-international units per milliliter (mIU/mL), are not taking hormones or oral contraceptives within 1 year, and are otherwise healthy. * Males who are sexually active and/or have partners of child-bearing age must use reliable methods of birth control during the study and until 3 months after the last doses of study medication. These requirements do not apply if a participant or his partner has been surgically sterilized or is not between menarche and 1 year postmenopausal.
Exclusion criteria
* Have severe gastrointestinal disease that may significantly affect gastric emptying or motility. * Previous histories or active diagnoses of pancreatitis. * Acute or chronic hepatitis, signs or symptoms of any other liver disease, or alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal (ULN). * Elevated total bilirubin (greater than 2 times ULN), clinically suspicious signs or symptoms of cirrhosis or history of cirrhosis. * Mean resting pulse rate (PR) less than 60 beats per minute (bpm) or greater than 100 bpm. * Current diagnosis or personal history of neuroendocrine tumors, family history of any type of multiple endocrine neoplasia, or Von Hippel-Lindau disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 6 Weeks in Mean 24-Hour Systolic Blood Pressure | Baseline, 6 Weeks | Systolic blood pressure obtained from Ambulatory Blood Pressure Monitoring (ABPM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 6 Weeks in Mean 24-Hour Diastolic Blood Pressure | Baseline, 6 Weeks | Diastolic blood pressure obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. |
| Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | Baseline, 6 Weeks | Pulse rate obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. |
| Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | Baseline, 6 Weeks | Pulse Pressures obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. |
| Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 | Days 7, 21, 42, 70, 77, 91, 112, 140; Predose and Days 7 and 77: 1 hour Postdose. | Population pharmacokinetic parameter, apparent volume of distribution (V/F) is a theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Apparent volume of distribution (V/F) was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups. |
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, 6 Weeks | LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. |
| Population Pharmacokinetics: Apparent Clearance of LY2409021 | Days 7, 21, 42, 70, 77, 91, 112, 140; 15 minute Predose and Days 7 and 77: 1 hour Postdose. | Population pharmacokinetic parameter apparent clearance (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time and was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups. |
| Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | Baseline, 6 Weeks | Mean Arterial Pressures obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate. |
Countries
Czechia, Mexico, Poland, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LY2409021 20 mg Period 1: Single daily dose of 20 mg LY2409021 administered orally for 6 Weeks; Wash-out: 4 weeks; Period 2: Single daily dose of placebo administered orally for 6 weeks. | 133 |
| Placebo Period 1: Single daily dose of placebo administered orally for 6 weeks; Wash-out: 4 weeks; Period 2: Single daily dose of 20 mg Ly2409021 administered orally for 6 weeks. | 137 |
| Total | 270 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 2 | 0 |
| Period 1 | Lost to Follow-up | 0 | 1 |
| Period 1 | Protocol Violation | 1 | 0 |
| Period 1 | Withdrawal by Subject | 2 | 3 |
| Period 2 | Adverse Event | 1 | 0 |
| Period 2 | Lost to Follow-up | 0 | 1 |
| Period 2 | Withdrawal by Subject | 1 | 1 |
| Wash-out | Lost to Follow-up | 1 | 1 |
| Wash-out | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | LY2409021 20 mg |
|---|---|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 8.9 | 57.7 years STANDARD_DEVIATION 8.9 | 58.3 years STANDARD_DEVIATION 8.9 |
| Diagnosis of Hypertension No | 44 Participants | 88 Participants | 44 Participants |
| Diagnosis of Hypertension Yes | 93 Participants | 182 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 62 Participants | 125 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 69 Participants | 130 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 15 Participants | 9 Participants |
| Hemoglobin A1c (HBA1c) < 7.5% | 86 Participants | 170 Participants | 84 Participants |
| Hemoglobin A1c (HBA1c) ≥ 7.5 % | 51 Participants | 100 Participants | 49 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 22 Participants | 42 Participants | 20 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants | 35 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 9 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 87 Participants | 179 Participants | 92 Participants |
| Region of Enrollment Czechia | 22 Participants | 41 Participants | 19 Participants |
| Region of Enrollment Mexico | 23 Participants | 47 Participants | 24 Participants |
| Region of Enrollment Poland | 18 Participants | 36 Participants | 18 Participants |
| Region of Enrollment United States | 74 Participants | 146 Participants | 72 Participants |
| Sex: Female, Male Female | 60 Participants | 117 Participants | 57 Participants |
| Sex: Female, Male Male | 77 Participants | 153 Participants | 76 Participants |
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 | 49 / 258 | 32 / 256 | 25 / 249 | 30 / 253 |
| serious Total, serious adverse events | 4 / 258 | 2 / 256 | 2 / 249 | 4 / 253 |
Outcome results
Primary
Change From Baseline to 6 Weeks in Mean 24-Hour Systolic Blood Pressure
Systolic blood pressure obtained from Ambulatory Blood Pressure Monitoring (ABPM).
Time frame: Baseline, 6 Weeks
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour Systolic Blood Pressure | 2.79 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour Systolic Blood Pressure | 0.53 mmHg |
p-value: <0.00195% CI: [1.11, 3.4]Mixed Models Analysis
Secondary
Change From Baseline in Hemoglobin A1c (HbA1c)
LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate.
Time frame: Baseline, 6 Weeks
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LY2409021 20 mg | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.65 percentage of HbA1c |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.16 percentage of HbA1c |
Secondary
Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP)
Mean Arterial Pressures obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate.
Time frame: Baseline, 6 Weeks
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | 24 Hour MAP | 1.83 mmHg |
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | Daytime MAP | 2.04 mmHg |
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | Nighttime MAP | 1.31 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | 24 Hour MAP | 0.17 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | Daytime MAP | 0.08 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Mean Arterial Pressures (MAP) | Nighttime MAP | 0.33 mmHg |
Secondary
Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate
Pulse rate obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate.
Time frame: Baseline, 6 Weeks
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | 24 Hour Pulse Rate | 0.46 beats/minute |
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | Mean Daytime Pulse Rate | 0.74 beats/minute |
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | Mean Nighttime Pulse Rate | -0.39 beats/minute |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | 24 Hour Pulse Rate | 0.43 beats/minute |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | Mean Daytime Pulse Rate | 0.56 beats/minute |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Peripheral Pulse Rate | Mean Nighttime Pulse Rate | -0.04 beats/minute |
Secondary
Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures
Pulse Pressures obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate.
Time frame: Baseline, 6 Weeks
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | 24-Hour Pulse Pressure | 1.51 mmHg |
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | Daytime Pulse Pressure | 1.49 mmHg |
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | Nighttime Pulse Pressure | 1.51 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | 24-Hour Pulse Pressure | 0.62 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | Daytime Pulse Pressure | 0.54 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour, Daytime, and Nighttime Pulse Pressures | Nighttime Pulse Pressure | 0.80 mmHg |
Secondary
Change From Baseline to 6 Weeks in Mean 24-Hour Diastolic Blood Pressure
Diastolic blood pressure obtained from Ambulatory Blood Pressure Monitoring (ABPM). LS Mean of treatment differences, adjusted for country, diagnosis of hypertension, sequence, treatment, period, time within period, treatment by time within period interaction, and the baseline measurement as covariate.
Time frame: Baseline, 6 Weeks
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LY2409021 20 mg | Change From Baseline to 6 Weeks in Mean 24-Hour Diastolic Blood Pressure | 1.37 mmHg |
| Placebo | Change From Baseline to 6 Weeks in Mean 24-Hour Diastolic Blood Pressure | 0.00 mmHg |
p-value: <0.0195% CI: [0.66, 2.08]Mixed Models Analysis
Secondary
Population Pharmacokinetics: Apparent Clearance of LY2409021
Population pharmacokinetic parameter apparent clearance (CL/F) is the apparent volume of the body fluid cleared of the drug per unit of time and was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups.
Time frame: Days 7, 21, 42, 70, 77, 91, 112, 140; 15 minute Predose and Days 7 and 77: 1 hour Postdose.
Population: Modified intent-to-treat (mITT) population consisting of all randomized subjects who received at least one dose of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2409021 20 mg | Population Pharmacokinetics: Apparent Clearance of LY2409021 | 0.406 Liter per hour (L/hr) | Geometric Coefficient of Variation 30.7 |
Secondary
Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021
Population pharmacokinetic parameter, apparent volume of distribution (V/F) is a theoretical volume that a drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Apparent volume of distribution (V/F) was estimated by modeling of LY2409021 plasma concentration data from all LY2409021 groups.
Time frame: Days 7, 21, 42, 70, 77, 91, 112, 140; Predose and Days 7 and 77: 1 hour Postdose.
Population: All randomized participants who received at least 1 one dose of study drug and had at least one measureable drug concentration.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| LY2409021 20 mg | Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 | 36.7 Liters | Geometric Coefficient of Variation 23.2 |