Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this study is to measure the effect of LY2189265 to increase insulin levels in response to glucose intake.
Interventions
DRUGGlucagon
Administered intravenously
BIOLOGICALLY2189265
Administered subcutaneously
DRUGPlacebo
Administered subcutaneously
DRUGInsulin
Administered intravenously
DRUGGlucose
Administered intravenously
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
All Participants * Women must be surgically sterile (hysterectomy or bilateral oophorectomy or tubal ligation) or postmenopausal as defined by age \>45 years without use of oral contraceptive agents for greater than 1 year and have either: * spontaneous amenorrhea greater than 12 months, or * spontaneous amenorrhea 6 to 12 months with documented follicle stimulating hormone (FSH) \>25 milli international units/milliliter (mIU/mL) and serum estradiol \<73 picomoles/liter (pmol/L) (20 picograms/milliliter \[pg/mL\]) * Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures * Have given written informed consent approved by Lilly and the ethical review board governing the site * Have serum creatinine \<150 micromoles/liter (µmol/L) (\<1.3 milligrams/deciliter \[mg/dl\] in women, \<170 µmol/L \[\<1.5 mg/dL\] in men) * Have normal hemoglobin result, as determined by the investigator Healthy Participants * Overtly healthy men and women as determined by medical history, normal lab results and physical examination. * Body mass index (BMI) between 19 and 25 kilograms/meter squared (kg/m\^2), inclusive. * Normal blood pressure and heart rate as determined by the investigator * Have a normal response to an oral glucose tolerance test (OGTT) (glucose \<7.8 millimoles/liter \[mmol/L\] \[\<140 mg/dL\] at 2 hours after 75 grams (g) oral glucose load) Participants with type 2 diabetes mellitus (T2DM) * Participants will have a BMI between 22.0 and 40.0 kg/m\^2 * Have T2DM controlled with diet and exercise alone or metformin for at least 4 weeks prior to admission * Have a hemoglobin A1c (HbA1c) value at screening (or within 4 weeks prior to screening) of 6.0% to 9.5% * Diagnosed with T2DM within the past 10 years * Clinical laboratory test results within normal range or deemed clinically insignificant by the Investigator. Abnormalities of serum glucose, serum lipids, urinary glucose, and urinary protein consistent with T2DM are acceptable. * Participants who are taking stable-dose prescription medications (for example, antihypertensive agents, aspirin, lipid-lowering agents) for treatment of concurrent medical conditions are permitted to participate providing the medication is not associated with development of torsade de pointes. However, use of beta-blockers and thiazide diuretics are not permitted during this study.
Exclusion criteria
All Participants * Within 30 days of the initial dose of study drug, have received treatment with a drug that has not received regulatory approval for any indication * Known allergies to Glucagon-Like Peptide 1 (GLP-1) related compounds * Have previously completed or withdrawn from this study or any other study in the last year investigating glucagon-like peptides or incretin mimetics including exenatide (Byetta®) * Regular use of known drugs of abuse and/or positive findings on urinary drug screening, other than findings consistent with medication prescribed by the participant's physician(s) * History or presence of cardiovascular, respiratory, renal, endocrine (except T2DM), hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs or of constituting a risk when taking the study medication or interfering with the interpretation of data * Have a history or presence of gastrointestinal disorder * Poorly controlled hypertension (systolic greater than 160 millimeters of mercury \[mmHg\], diastolic greater than 95 mmHg) and/or evidence of labile blood pressure including symptomatic postural hypotension. Use of beta-blockers or thiazide diuretics is not permitted during the study * Have a clinically significant history of cardiac disease or presence of active cardiac disease within 1 year of the screening period * Evidence of hepatitis C and/or positive hepatitis C antibody * Evidence of hepatitis B and/or positive hepatitis B surface antigen * Evidence of human immunodeficiency virus (HIV) and/or positive for HIV antibodies * Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 units per week (females) or are unwilling to follow alcohol restrictions (1 unit = 12 ounces \[oz\] or 360 milliliters\[mL\] of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits). * Smoke more than 10 cigarettes or equivalent in nicotine use or nicotine substitutes per day * Regular use of systemic corticosteroids by oral, intravenous, or intramuscular route, or potent, inhaled, or intranasal steroids known to have a high rate of systemic absorption * Have a history or presence of significant active neuropsychiatric disease * Blood donation of more than 500 mL in the last 3 months or any blood donation within the last month * Any other condition, which in the opinion of the investigator would preclude participation in the study * An abnormality in the 12-lead electrocardiogram (ECG) that in the opinion of the investigator increases the risk of participating in the study. * Any clinically significant abnormal hematology, clinical chemistry, or urinary result(s) as determined by the investigator * Evidence of significant active uncontrolled endocrine or autoimmune abnormalities (for example thyroid disease, or pernicious anemia) as judged by the screening physician Healthy Participants * Intended use of over-the-counter or prescription medication 7 and 14 days, respectively, prior to dosing. Participants with T2DM * Clinically significant peripheral vascular occlusive disease (PVOD). * Known severe exudative diabetic retinopathy * Known significant autonomic neuropathy as evidenced by urinary retention, diabetic diarrhea, or gastroparesis * Have experienced a ketoacidotic episode (pH less than 7.3) requiring hospitalization in the last 6 months * Outpatient use of insulin for control of diabetes within the past 2 years * Use of antidiabetic agents other than metformin in the 4 weeks prior to study entry or use of thiazolidinediones within 12 weeks of study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Insulin Concentration (Cmax) - First Phase Response | 0-10 minutes after dextrose bolus on Day 3 postdose | On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 0 to 10 minutes (INSCmax\[0-10\]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus. |
| Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response | 0-10 minutes after dextrose bolus on Day 3 postdose | On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Area under the plasma insulin concentration time curve from 0 to 10 minutes (INSAUC\[0-10\]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus. |
| Maximum Insulin Concentration (Cmax) - Second Phase Response | 10-180 minutes after dextrose bolus on Day 3 postdose | On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 10 to 180 minutes (INSCmax\[10-180\]) following the first dextrose bolus (the second phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus. |
| Insulin Area Under the Curve (AUC) - Second Phase Response | 10-180 minutes after dextrose bolus on Day 3 post dose | On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Area under the plasma insulin concentration time curve from 10 to 180 minutes (INSAUC\[10-180\]) following the first dextrose bolus (the second phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Maximum Concentration (Cmax) | After glucagon bolus on Day 3 postdose | On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. Maximum plasma insulin concentration from -2 to 20 minutes following the glucagon bolus (INSCmaxG) is presented. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Insulin Concentration-time Curve (AUC) | After glucagon bolus on Day 3 postdose | On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. Area under the plasma insulin concentration-time curve from -2 to 20 minutes following the glucagon bolus (INSAUCG) is presented. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Participants Includes healthy participants randomized to receive 1.5 milligram (mg) LY2189265 (Dulaglutide) first or Placebo first on Day 1 of either treatment sequence. | 10 |
| Participants With Type 2 Diabetes Mellitus (T2DM) Includes participants with T2DM randomized to receive 1.5 mg LY2189265 (Dulaglutide) first or Placebo first on Day 1 of either treatment sequence. | 22 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 of Study: First Intervention | Adverse Event | 0 | 1 |
| Period 1 of Study: First Intervention | Withdrawal by Subject | 1 | 0 |
| Period 2 of Study: Second Intervention | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Healthy Participants | Total | Participants With Type 2 Diabetes Mellitus (T2DM) |
|---|---|---|---|
| Age, Continuous | 51.9 years STANDARD_DEVIATION 5 | 54.9 years STANDARD_DEVIATION 6.1 | 56.3 years STANDARD_DEVIATION 6.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 32 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 10 Participants | 32 Participants | 22 Participants |
| Region of Enrollment Germany | 10 participants | 32 participants | 22 participants |
| Sex: Female, Male Female | 3 Participants | 10 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 22 Participants | 15 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 | 2 / 10 | 6 / 10 | 9 / 21 | 11 / 21 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 21 | 0 / 21 |
Outcome results
Primary
Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response
On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Area under the plasma insulin concentration time curve from 0 to 10 minutes (INSAUC\[0-10\]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.
Time frame: 0-10 minutes after dextrose bolus on Day 3 postdose
Population: All participants (healthy and with type 2 diabetes mellitus \[T2DM\]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSAUC(0-10) first phase response data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Healthy Participants: Placebo | Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response | 22.9 picomole times hour per liter (pmol*h/L) |
| Healthy Participants: LY2189265 | Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response | 70.7 picomole times hour per liter (pmol*h/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): Placebo | Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response | 5.06 picomole times hour per liter (pmol*h/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265 | Area Under the Insulin Concentration-time Curve (AUC) - First Phase Response | 40.1 picomole times hour per liter (pmol*h/L) |
p-value: <0.00195% CI: [2.66, 3.59]Mixed Models Analysis
p-value: <0.00195% CI: [4.82, 13]Mixed Models Analysis
Primary
Insulin Area Under the Curve (AUC) - Second Phase Response
On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Area under the plasma insulin concentration time curve from 10 to 180 minutes (INSAUC\[10-180\]) following the first dextrose bolus (the second phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.
Time frame: 10-180 minutes after dextrose bolus on Day 3 post dose
Population: All participants (healthy and with type 2 diabetes mellitus \[T2DM\]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSAUC(10-180) second response phase data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Healthy Participants: Placebo | Insulin Area Under the Curve (AUC) - Second Phase Response | 68.8 picomole times hour per liter (pmol*h/L) |
| Healthy Participants: LY2189265 | Insulin Area Under the Curve (AUC) - Second Phase Response | 141 picomole times hour per liter (pmol*h/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): Placebo | Insulin Area Under the Curve (AUC) - Second Phase Response | 147 picomole times hour per liter (pmol*h/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265 | Insulin Area Under the Curve (AUC) - Second Phase Response | 357 picomole times hour per liter (pmol*h/L) |
p-value: 0.01195% CI: [1.26, 3.31]Mixed Models Analysis
p-value: <0.00195% CI: [1.71, 3.47]Mixed Models Analysis
Primary
Maximum Insulin Concentration (Cmax) - First Phase Response
On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 0 to 10 minutes (INSCmax\[0-10\]) following the first dextrose bolus (the first phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.
Time frame: 0-10 minutes after dextrose bolus on Day 3 postdose
Population: All participants (healthy and with type 2 diabetes mellitus \[T2DM\]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSCmax(0-10) first response phase data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Healthy Participants: Placebo | Maximum Insulin Concentration (Cmax) - First Phase Response | 233 picomole per liter (pmol/L) |
| Healthy Participants: LY2189265 | Maximum Insulin Concentration (Cmax) - First Phase Response | 689 picomole per liter (pmol/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): Placebo | Maximum Insulin Concentration (Cmax) - First Phase Response | 74.3 picomole per liter (pmol/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265 | Maximum Insulin Concentration (Cmax) - First Phase Response | 401 picomole per liter (pmol/L) |
p-value: <0.00195% CI: [2.41, 3.64]Mixed Models Analysis
p-value: <0.00195% CI: [4.09, 7.13]Mixed Models Analysis
Primary
Maximum Insulin Concentration (Cmax) - Second Phase Response
On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. On Day 3 of each treatment period, participants underwent a 6-hour insulin infusion, followed by an intravenous (IV) dextrose 50% bolus to stimulate insulin secretion. Three hours later, participants were administered a second dextrose bolus, followed by an infusion of 20% dextrose and, 15 minutes after the start of the 20% dextrose infusion, a 1-mg glucagon bolus was administered. Maximum plasma insulin concentration from 10 to 180 minutes (INSCmax\[10-180\]) following the first dextrose bolus (the second phase response) was corrected for baseline, where baseline was the mean of the insulin concentrations obtained between -30 and 0 minutes relative to the first dextrose bolus.
Time frame: 10-180 minutes after dextrose bolus on Day 3 postdose
Population: All participants (healthy and with type 2 diabetes mellitus \[T2DM\]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSCmax(10-180) second response phase data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Healthy Participants: Placebo | Maximum Insulin Concentration (Cmax) - Second Phase Response | 89.2 picomole per liter (pmol/L)] |
| Healthy Participants: LY2189265 | Maximum Insulin Concentration (Cmax) - Second Phase Response | 370 picomole per liter (pmol/L)] |
| Participants With Type 2 Diabetes Mellitus (T2DM): Placebo | Maximum Insulin Concentration (Cmax) - Second Phase Response | 95.9 picomole per liter (pmol/L)] |
| Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265 | Maximum Insulin Concentration (Cmax) - Second Phase Response | 363 picomole per liter (pmol/L)] |
p-value: <0.00195% CI: [3.45, 5]Mixed Models Analysis
p-value: <0.00195% CI: [2.99, 4.78]Mixed Models Analysis
Secondary
Insulin Maximum Concentration (Cmax)
On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. Maximum plasma insulin concentration from -2 to 20 minutes following the glucagon bolus (INSCmaxG) is presented.
Time frame: After glucagon bolus on Day 3 postdose
Population: All participants (healthy or with type 2 diabetes mellitus \[T2DM\]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSCmaxG data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Healthy Participants: Placebo | Insulin Maximum Concentration (Cmax) | 996 picomole per liter (pmol/L) |
| Healthy Participants: LY2189265 | Insulin Maximum Concentration (Cmax) | 1215 picomole per liter (pmol/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): Placebo | Insulin Maximum Concentration (Cmax) | 1088 picomole per liter (pmol/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265 | Insulin Maximum Concentration (Cmax) | 1514 picomole per liter (pmol/L) |
p-value: 0.02195% CI: [1.04, 1.43]Mixed Models Analysis
p-value: <0.00195% CI: [1.27, 1.53]Mixed Models Analysis
Other Pre-specified
Area Under the Insulin Concentration-time Curve (AUC)
On Day 1 of each treatment period, all participants (healthy or with type 2 diabetes mellitus \[T2DM\]) received a single subcutaneous dose of either LY2189265 or placebo. Area under the plasma insulin concentration-time curve from -2 to 20 minutes following the glucagon bolus (INSAUCG) is presented.
Time frame: After glucagon bolus on Day 3 postdose
Population: All participants (healthy or with type 2 diabetes mellitus \[T2DM\]) who received at least 1 dose of study drug (LY2189265 or Placebo) with evaluable INSAUCG data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Healthy Participants: Placebo | Area Under the Insulin Concentration-time Curve (AUC) | 239 picomole times hour per liter (pmol*h/L) |
| Healthy Participants: LY2189265 | Area Under the Insulin Concentration-time Curve (AUC) | 341 picomole times hour per liter (pmol*h/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): Placebo | Area Under the Insulin Concentration-time Curve (AUC) | 236 picomole times hour per liter (pmol*h/L) |
| Participants With Type 2 Diabetes Mellitus (T2DM): LY2189265 | Area Under the Insulin Concentration-time Curve (AUC) | 414 picomole times hour per liter (pmol*h/L) |
p-value: 0.00995% CI: [1.14, 1.8]Mixed Models Analysis
p-value: <0.00195% CI: [1.59, 1.94]Mixed Models Analysis