A Study of LY2409021 in Patients With Type 2 Diabetes

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01241448
• Collaborator: (none)
• Enrollment: 263
• Locations: 40
• Arms: 4
• Duration (Months): 14
• Patients Per Site: 6.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

LY2409021 is being evaluated for possible treatment in type 2 diabetes. This study is designed to compare LY2409021 given alone or given in combination with metformin against placebo the change in hemoglobin A1c after a 24-week treatment period.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: LY2409021; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 263 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Phase 2b Study of LY2409021 in Patients With Type 2 Diabetes Mellitus
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Taken orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	Drug: Placebo; Administered Orally
Experimental: 2.5 mg LY2409021 Taken orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	Drug: LY2409021; Administered Orally
Experimental: 10 mg LY2409021 Taken orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	Drug: LY2409021; Administered Orally
Experimental: 20 mg LY2409021 Taken orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	Drug: LY2409021; Administered Orally

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c) [Baseline, 24 weeks]

   Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline HbA1c, metformin use, visit, and visit-by-treatment interaction.

Secondary Outcome Measures

1. Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG) [Baseline, 24 weeks]

   Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

2. Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile [Baseline, 24 weeks]

   SMBG profiles consisted of blood glucose values collected before and 2 hours after the 3 main meals and at 0300 hours (3:00 AM). Values represent mean of values collected same time on 3 separate days within a week prior to visit. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

3. Change From Baseline to 24 Week Endpoint in Plasma Glucose [Baseline, 24 weeks]

   Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

4. Change From Baseline to 24 Week Endpoint in Fasting Insulin [Baseline, 24 weeks]

   Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

5. Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total [Baseline, 24 weeks]

   GLP-1 is cleaved from proglucagon to form the active peptide GLP-1. The active form promotes suppression of glucagon secretion. Total GLP-1 is the active GLP-1 and the Dipeptidyl Peptidase IV cleaved GLP-1 form. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

6. Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile [Baseline, 24 weeks]

   Fasting Lipid Profile included: Triglycerides, Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C) and Total Cholesterol. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, visit, and visit-by-treatment interaction.

7. Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total) [Baseline, 24 weeks]

   Subfraction included: Very Low Density Lipoprotein (VLDL) Total. Least squares mean use an analysis of covariance model. The model included baseline lipoprotein subfractions, metformin use and treatment.

8. Change From Baseline to 24 Week Endpoint in Free Fatty Acids [Baseline, 24 weeks]

   Least squares mean use an analysis of covariance model. The model included baseline free fatty acid, metformin use and treatment.

9. Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) [Baseline, 24 weeks]

   HOMA-IR is a computer model (based on HOMA2) which uses fasting plasma insulin and glucose concentrations to estimate insulin resistance (HOMA-IR) as a proportion reference population (normal young adults). The normal reference population with normal function was indexed to 1.0. Higher values indicate increased insulin resistance. Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

10. Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B [Baseline, 24 week]

    HOMA-B is a computer model (based on HOMA-2) that uses fasting plasma insulin and glucose concentrations to estimate steady state pancreatic beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Higher values indicate greater beta cell function. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.

11. Change From Baseline to 24 Week Endpoint in Weight [Baseline, 24 weeks]

    Least squares means were adjusted for baseline weight, metformin use, visit, treatment and visit by treatment interaction.

12. Population Pharmacokinetics: Apparent Clearance (CL/F) of LY2409021 [Baseline up to 26 weeks]

    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.

13. Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 [Baseline up to 26 weeks]

    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.

14. The Percentage of Participants Experiencing a Hypoglycemic Episode [Baseline through 24 weeks]

    A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) [3.9 millimoles per liter (mmol/L)].

15. The 30-Day Adjusted Rate of Hypoglycemic Episodes [Baseline through 24 weeks]

    A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) [3.9 millimoles per liter (mmol/L)]. 30-day adjusted rate=(total number of episodes between 2 time intervals/number of days between intervals) X 30 days. Outcome measure was not analyzed due to the limited number of hypoglycemic events observed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have a diagnosis of Type 2 diabetes mellitus according to the World Health Organization (WHO) diagnostic criteria

• Are women not of child-bearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause.

• Are male patients using a reliable method of birth control during the study and until 3 months after the last dose of study medication.

• Are being treated with either diet and exercise alone, or with diet and exercise in combination with metformin. Metformin therapy must have been stable and unchanged for at least 3 months prior to screening and at a dose of at least 1000 milligram per day (mg/day).

• Have a hemoglobin A1c (HbA1c) value of 7.0% to 10.5%, inclusive.

• Have a body mass index (BMI) between 25 to 45 kilogram per meter squared (kg/m^2), inclusive.

In the opinion of the investigator, are capable and willing to:

• Perform self-monitoring of blood glucose

• Complete a study diary as required for this protocol

• Maintain consistent dietary, physical activity, and sleeping patterns throughout the duration of the study

• Comply with treatment regimens

• Have given written informed consent to participate in this study in accordance with local regulations and the Ethical Review Board (ERB) governing the study site.

Exclusion Criteria:

• Have more than 1 episode of severe hypoglycemia (defined as an event during which the patient requires the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) within 6 months prior to screening, or have a current diagnosis of hypoglycemia unawareness.

• Have had two or more emergency room visits or hospitalizations due to poor glucose control in the 6 months prior to screening.

• Have gastrointestinal disease that may significantly impact gastric emptying or motility or have undergone gastric bypass or gastric banding surgery.

• Have had a previous diagnosis of pancreatitis.

• Have New York Heart Association (NYHA) class II, III, or IV symptoms of heart failure

• Have a history of myocardial infarction, unstable angina, or a coronary revascularization procedure within 6 months of screening.

• Have a history of supraventricular tachycardia, ventricular tachycardia, or other cardiac arrhythmia.

• Have a history of transient ischemic attack (TIA) or stroke within 6 months of screening.

• Have poorly controlled hypertension (systolic blood pressure greater than or equal to 150 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg) as determined by the mean of three separate measurements.

• Show evidence of labile blood pressure, including symptomatic postural hypotension.

• Have any abnormality of the ECG that would impact patient safety or data interpretation.

• Show clinical signs or symptoms of liver disease, or liver function tests (LFTs; aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) greater than 2.5 times upper limit of normal (ULN) as determined by the central laboratory at screening.

• Have a current or previous diagnosis of Gilbert's disease.

• Have previous or current diagnosis of Hepatitis B or C

• Have a serum creatinine >2 milligrams per deciliter (mg/dL) or, in patients being treated with metformin, a serum creatinine above (or creatinine clearance below) what is approved in the metformin product labeling in the respective country.

• Show evidence of uncorrected hypothyroidism or hyperthyroidism based on clinical evaluation and/or an abnormal thyroid stimulating hormone result as determined by the central laboratory at screening; patients receiving dose-stable thyroid replacement therapy for at least 3 months prior to screening will be allowed to participate in the study.

• Have any other abnormal laboratory value that, in the opinion of the investigator, precludes the patient from participation in the study. Laboratory abnormalities consistent with type 2 diabetes mellitus and all other eligibility criteria are acceptable: for example, abnormalities of blood glucose, hemoglobin A1c (HbA1c), urinary glucose, and urinary protein (with a range of trace to 1+ on dipstick).

• Have a currently suspected or treated malignancy, or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years.

• Have a personal or family history of pancreatic neoplasia.

• Have non-fasting triglycerides >600 mg/dL.

• Use or have used insulin or GLP-1 agonists (for more than 1 week within the 3-month period prior to screening), or any oral antihyperglycemic medication (OAM) other than metformin within the 3-month period prior to screening.

• Currently use or intend to use prescription or over-the-counter medications, including herbal supplements, to promote weight loss or to regulate blood glucose.

• Have current chronic (>2 weeks) systemic glucocorticoid therapy (excluding ocular topical, other topical, inhaled preparations) or have received such therapy within 8 weeks prior to screening.

• Currently use hyperglycemia-causing agents, hypoglycemia-causing agents (other than metformin), class II and III antiarrythmic agents, agents that reduce gastrointestinal motility, central nervous system stimulants (with the exception of caffeinated beverages), fibrates, and niacin greater than or equal to 1 grams per day (gm/day).

• Have an average weekly alcohol intake that exceeds 2 units per day for males and 1 unit per day for females (1 unit = 12 ounces (oz) or 360 mL of beer; 5 oz or 150 milliliters (mL) of wine; 1.5 oz or 45 milliliter (mL) of distilled spirits).

• Currently use drugs with a narrow therapeutic index (for example, digoxin, lithium, phenytoin, theophylline, and warfarin).

• Currently use drugs that are known to prolong the QT interval.

• Currently use or intend to use potent inhibitors of CYP3A, which include but are not limited to atazanavir, indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, and telithromycin.

• Have previously completed or withdrawn from this study or any other study investigating LY2409021.

• Have known allergies to LY2409021 or related compounds.

• Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or unapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

• Have any other condition such as alcohol abuse, drug abuse, or psychiatric disorder that may affect the ability to participate in the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Burbank	California	United States	91505
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Concord	California	United States	94520
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fresno	California	United States	93720
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lakewood	California	United States	990712
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Los Angeles	California	United States	90057
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mission Hills	California	United States	91345
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Palm Springs	California	United States	92262
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Roseville	California	United States	95661
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Luis Obispo	California	United States	93401
10	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Idaho Falls	Idaho	United States	83404
11	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Meridian	Idaho	United States	83646
12	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Topeka	Kansas	United States	66606
13	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Saint Louis	Missouri	United States	63141
14	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Henderson	Nevada	United States	89052
15	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Charlotte	North Carolina	United States	28209
16	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Raleigh	North Carolina	United States	27609
17	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Wilmington	North Carolina	United States	28401
18	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Fargo	North Dakota	United States	58103
19	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Damme		Germany	49401
20	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Dresden		Germany	01307
21	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Elsterwerda		Germany	04910
22	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hohenmölsen		Germany	06679
23	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Ludwigshafen		Germany	67059
24	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Lüneburg		Germany	21339
25	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Mainz		Germany	55116
26	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chieti Scalo		Italy	66013
27	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Milano		Italy	20162
28	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hato Rey		Puerto Rico	00917
29	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Manati		Puerto Rico	00674
30	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Juan		Puerto Rico	00917-3104
31	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Baia Mare		Romania	430123
32	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Brasov		Romania	500365
33	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Bucharest		Romania	050538
34	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Iasi		Romania	700547
35	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Targu-Mures		Romania	540098
36	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Kosice		Slovakia	04012
37	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Malacky		Slovakia	90101
38	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Alcira		Spain	46600
39	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Alicante		Spain	03114
40	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Seville		Spain	41003

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-4559) or 1-317-615-4559 Mon - Fri 9 Am - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01241448
• Other Study ID Numbers: 13031; I1R-MC-GLBG
• First Posted: Nov 16, 2010
• Last Update Posted: Apr 24, 2018
• Last Verified: Mar 1, 2018

• Keywords provided by Eli Lilly and Company: Type 2 Diabetes Mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Period Title: Overall Study
STARTED	66	65	66	66
Intent-to-Treat Population (ITT)	63	63	64	64
ITT With ≥1 Post-Baseline Measure	61	61	64	62
COMPLETED	29	36	43	43
NOT COMPLETED	37	29	23	23

Baseline Characteristics

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021	Total
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	Total of all reporting groups
Overall Participants	63	63	64	64	254
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.0 (8.79)	57.3 (8.23)	54.6 (8.05)	55.9 (8.82)	55.7 (8.49)
Sex: Female, Male (Count of Participants)
Female	23 36.5%	24 38.1%	17 26.6%	19 29.7%	83 32.7%
Male	40 63.5%	39 61.9%	47 73.4%	45 70.3%	171 67.3%
Region of Enrollment (Count of Participants)
United States	29 46%	25 39.7%	26 40.6%	28 43.8%	108 42.5%
Slovakia	7 11.1%	7 11.1%	6 9.4%	6 9.4%	26 10.2%
Puerto Rico	3 4.8%	4 6.3%	3 4.7%	5 7.8%	15 5.9%
Spain	6 9.5%	7 11.1%	7 10.9%	7 10.9%	27 10.6%
Romania	10 15.9%	12 19%	12 18.8%	10 15.6%	44 17.3%
Germany	7 11.1%	7 11.1%	9 14.1%	6 9.4%	29 11.4%
Italy	1 1.6%	1 1.6%	1 1.6%	2 3.1%	5 2%
Race (Count of Participants)
Asian	1 1.6%	3 4.8%	1 1.6%	0 0%	5 2%
Black or African American	4 6.3%	6 9.5%	2 3.1%	6 9.4%	18 7.1%
White	58 92.1%	54 85.7%	61 95.3%	58 90.6%	231 90.9%
Ethnicity (Count of Participants)
Hispanic or Latino	16 25.4%	14 22.2%	13 20.3%	13 20.3%	56 22%
Not Hispanic or Latino	36 57.1%	31 49.2%	35 54.7%	37 57.8%	139 54.7%
Not Reported	11 17.5%	18 28.6%	16 25%	14 21.9%	59 23.2%
Diabetes Duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.8 (5.29)	6.9 (7.23)	5.5 (4.21)	5.8 (6.13)	6.0 (5.81)
Body Mass Index (BMI) (kilograms per meter squared (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per meter squared (kg/m^2)]	32.1 (4.63)	31.9 (4.86)	32.3 (4.91)	32.6 (5.27)	32.2 (4.90)
Waist Circumference (centimeters (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters (cm)]	106.7 (12.41)	107.5 (11.16)	107.2 (12.24)	106.8 (12.28)	107.1 (11.97)
Hemoglobin A1c (HbA1c) (percentage of Hemoglobin A1c (HbA1c)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of Hemoglobin A1c (HbA1c)]	8.1 (1.00)	8.1 (0.93)	8.1 (0.87)	8.0 (0.92)	8.0 (0.92)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 24 Week Endpoint in Hemoglobin A1c (HbA1c)
Description	Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline HbA1c, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All participants randomly assigned to treatment with at least 1 post-baseline HbA1c measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the participants were randomly assigned.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	61	61	63	60
Least Squares Mean (90% Confidence Interval) [percentage of Hemoglobin A1c (HbA1c)]	-0.15	-0.45	-0.78	-0.92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 2.5 mg LY2409021
	Comments	Sixty-five randomized patients (45 completers) per arm were expected to provide at least 90% power to detect 0.8% HbA1c difference with placebo assuming a SD for change in HbA1c of 1.2% (0.05 1-sided type I error).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.094
	Comments	No multiplicity adjustments were used to calculate the p-value.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 90%; -0.58 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 10 mg LY2409021
	Comments	Sixty-five randomized patients (45 completers) per arm were expected to provide at least 90% power to detect 0.8% HbA1c difference with placebo assuming a SD for change in HbA1c of 1.2% (0.05 1-sided type I error).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No multiplicity adjustments were used to calculate the p-value.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 90%; -0.90 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, 20 mg LY2409021
	Comments	Sixty-five randomized patients (45 completers) per arm were expected to provide at least 90% power to detect 0.8% HbA1c difference with placebo assuming a SD for change in HbA1c of 1.2% (0.05 1-sided type I error).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	No multiplicity adjustments were used to calculate the p-value.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.77
	Confidence Interval	(2-Sided) 90%; -1.05 to -0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Fasting Blood Glucose (FBG)
Description	Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All participants randomly assigned to treatment with at least 1 post-baseline laboratory FBG measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomly assigned.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	60	59	62	60
Least Squares Mean (95% Confidence Interval) [millimoles per liter (mmol/L)]	-0.36	-0.46	-1.07	-1.14

3. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in 7-point Self Monitored Glucose (SMBG) Profile
Description	SMBG profiles consisted of blood glucose values collected before and 2 hours after the 3 main meals and at 0300 hours (3:00 AM). Values represent mean of values collected same time on 3 separate days within a week prior to visit. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline self-monitored glucose measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	54	56	59	59
Pre-morning meal (fasting)	-14.45	-15.76	-29.65	-32.55
2 hours after morning meal	-28.75	-23.01	-48.12	-45.76
Pre-mid-day meal	-17.83	-16.13	-27.35	-25.45
2 hours after mid-day meal	-23.75	-21.17	-31.42	-39.60
Pre-evening meal	-7.45	-11.77	-14.15	-25.02
2 hours after evening meal	-19.48	-21.74	-33.93	-32.01
0300 hours (3:00 AM)	-5.13	-9.52	-23.33	-25.67

4. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Plasma Glucose
Description	Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline plasma glucose measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	60	59	62	60
Least Squares Mean (95% Confidence Interval) [millimoles per liter (mmol/L)]	-0.36	-0.46	-1.07	-1.14

5. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Fasting Insulin
Description	Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline fasting insulin measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	55	58	60	59
Least Squares Mean (95% Confidence Interval) [picomoles per liter (pmol/L)]	10.62	2.61	14.95	9.65

6. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Fasting Glucagon-like Peptide 1 (GLP-1) Active and Total
Description	GLP-1 is cleaved from proglucagon to form the active peptide GLP-1. The active form promotes suppression of glucagon secretion. Total GLP-1 is the active GLP-1 and the Dipeptidyl Peptidase IV cleaved GLP-1 form. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline GLP-1 active and total measurements (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	56	58	62	59
Active GLP-1	-0.30	0.13	0.38	0.31
Total GLP-1	-0.12	1.84	4.63	8.23

7. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Fasting Lipid Profile
Description	Fasting Lipid Profile included: Triglycerides, Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C) and Total Cholesterol. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline fasting lipid measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	56	59	62	59
Triglycerides	-0.11	0.07	0.06	0.08
LDL-C	0.20	0.05	0.02	0.10
HDL-C	0.03	0.02	0.05	0.04
Total Cholesterol	0.15	0.10	0.10	0.19

8. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Lipoprotein Subfractions-Particles (Total)
Description	Subfraction included: Very Low Density Lipoprotein (VLDL) Total. Least squares mean use an analysis of covariance model. The model included baseline lipoprotein subfractions, metformin use and treatment.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline lipoprotein subfractions measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized, last observation carried forward (LOCF) principle was applied.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	52	59	61	55
Least Squares Mean (Standard Error) [nanomoles per liter (nmol/L)]	1.90 (4.296)	6.48 (4.048)	0.07 (4.099)	2.04 (4.328)

9. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Free Fatty Acids
Description	Least squares mean use an analysis of covariance model. The model included baseline free fatty acid, metformin use and treatment.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline free fatty acid measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	51	56	60	56
Least Squares Mean (Standard Error) [picomoles per liter (pmol/L)]	-0.04 (0.043)	-0.02 (0.040)	-0.15 (0.037)	-0.07 (0.040)

10. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint Indices in Insulin Sensitivity Using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
Description	HOMA-IR is a computer model (based on HOMA2) which uses fasting plasma insulin and glucose concentrations to estimate insulin resistance (HOMA-IR) as a proportion reference population (normal young adults). The normal reference population with normal function was indexed to 1.0. Higher values indicate increased insulin resistance. Least squares means of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline HOMA-IR measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	52	57	54	55
Least Squares Mean (95% Confidence Interval) [proportion of normal reference populatio]	0.19	0.02	0.26	0.19

11. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint Indices in Beta-cell Function Using HOMA-B
Description	HOMA-B is a computer model (based on HOMA-2) that uses fasting plasma insulin and glucose concentrations to estimate steady state pancreatic beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Higher values indicate greater beta cell function. Least squares (LS) mean of the change from baseline is from a mixed-model repeated measures analysis (MMRM). The model included terms for treatment group, baseline value, metformin use, visit, and visit-by-treatment interaction.
Time Frame	Baseline, 24 week

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline HOMA-B measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	52	57	54	55
Least Squares Mean (95% Confidence Interval) [percent of normal reference population]	4.88	7.90	17.69	16.39

12. Secondary Outcome

Title	Change From Baseline to 24 Week Endpoint in Weight
Description	Least squares means were adjusted for baseline weight, metformin use, visit, treatment and visit by treatment interaction.
Time Frame	Baseline, 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients with at least 1 post-baseline weight measurement (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	61	61	64	61
Least Squares Mean (95% Confidence Interval) [kilograms (kg)]	-1.07	-0.33	0.55	0.07

13. Secondary Outcome

Title	Population Pharmacokinetics: Apparent Clearance (CL/F) of LY2409021
Description	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	Baseline up to 26 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least 1 one dose of study drug (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	LY2409021
Arm/Group Description	2.5 mg, 10 mg or 20 mg LY2409021 taken orally once daily for 24 weeks
Measure Participants	191
Geometric Mean (Geometric Coefficient of Variation) [liters per hour (L/hr)]	0.486 (31.0)

14. Secondary Outcome

Title	Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021
Description	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	Baseline up to 26 weeks

Outcome Measure Data

Analysis Population Description

All randomized patients who received at least 1 one dose of study drug (excluding participant data from the excluded site); analyzed according to the treatment to which the patients were randomized.

Arm/Group Title	LY2409021
Arm/Group Description	2.5 mg, 10 mg or 20 mg LY2409021 taken orally once daily for 24 weeks
Measure Participants	191
Geometric Mean (Geometric Coefficient of Variation) [liters (L)]	33.4 (23.9)

15. Secondary Outcome

Title	The Percentage of Participants Experiencing a Hypoglycemic Episode
Description	A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) [3.9 millimoles per liter (mmol/L)].
Time Frame	Baseline through 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of study drug (excluding participant data from the excluded site).

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	63	63	64	64
Number [percentage of participants]	3.2 5.1%	6.3 10%	9.4 14.7%	7.8 12.2%

16. Secondary Outcome

Title	The 30-Day Adjusted Rate of Hypoglycemic Episodes
Description	A hypoglycemic episode is any event during which typical symptoms of hypoglycemia are observed or when the measured plasma glucose concentration is less than or equal to 70 milligrams per deciliter (mg/dL) [3.9 millimoles per liter (mmol/L)]. 30-day adjusted rate=(total number of episodes between 2 time intervals/number of days between intervals) X 30 days. Outcome measure was not analyzed due to the limited number of hypoglycemic events observed.
Time Frame	Baseline through 24 weeks

Outcome Measure Data

Analysis Population Description

Outcome measure was not analyzed due to the limited number of hypoglycemic events observed; therefore zero participants were analyzed.

Arm/Group Title	Placebo	2.5 mg LY2409021	10 mg LY2409021	20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.	20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
Measure Participants	0	0	0	0

Adverse Events

Arm/Group Title	Placebo		2.5 mg LY2409021		10 mg LY2409021		20 mg LY2409021
Arm/Group Description	Placebo orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.		2.5 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.		10 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.		20 mg LY2409021 orally once daily for 24 weeks. Participants who entered the study on stable metformin therapy were to continue at the dose prescribed by their physician.
All Cause Mortality
	Placebo		2.5 mg LY2409021		10 mg LY2409021		20 mg LY2409021
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		2.5 mg LY2409021		10 mg LY2409021		20 mg LY2409021
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/66 (4.5%)		0/65 (0%)		2/66 (3%)		2/66 (3%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Cardiac disorders
Atrial fibrillation	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Gastrointestinal disorders
Gastritis	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Ileus	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Infections and infestations
Pyelonephritis acute	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Investigations
Alanine aminotransferase increased	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	2
Aspartate aminotransferase increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	1/66 (1.5%)	1
Surgical and medical procedures
Cholecystectomy	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		2.5 mg LY2409021		10 mg LY2409021		20 mg LY2409021
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/66 (34.8%)		31/65 (47.7%)		34/66 (51.5%)		29/66 (43.9%)
Blood and lymphatic system disorders
Thrombocytopenia	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Cardiac disorders
Myocardial ischaemia	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Sinus bradycardia	0/66 (0%)	0	1/65 (1.5%)	2	0/66 (0%)	0	0/66 (0%)	0
Sinus tachycardia	0/66 (0%)	0	1/65 (1.5%)	1	2/66 (3%)	2	1/66 (1.5%)	1
Tachycardia	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Ventricular extrasystoles	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	2/66 (3%)	2
Congenital, familial and genetic disorders
Type ii hyperlipidaemia	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	1/66 (1.5%)	1
Type v hyperlipidaemia	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	2	0/66 (0%)	0
Ear and labyrinth disorders
Vertigo	2/66 (3%)	2	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Eye disorders
Conjunctivitis	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	2	0/66 (0%)	0
Eye haemorrhage	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Glaucoma	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	1/66 (1.5%)	1
Abdominal distension	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Abdominal pain	0/66 (0%)	0	1/65 (1.5%)	2	1/66 (1.5%)	1	0/66 (0%)	0
Abdominal pain upper	1/66 (1.5%)	1	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Constipation	2/66 (3%)	2	3/65 (4.6%)	5	0/66 (0%)	0	2/66 (3%)	6
Diarrhoea	2/66 (3%)	2	2/65 (3.1%)	2	4/66 (6.1%)	4	2/66 (3%)	2
Dry mouth	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Dyspepsia	0/66 (0%)	0	1/65 (1.5%)	1	1/66 (1.5%)	1	0/66 (0%)	0
Flatulence	1/66 (1.5%)	1	1/65 (1.5%)	2	2/66 (3%)	2	1/66 (1.5%)	1
Food poisoning	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Gastritis	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Gastrooesophageal reflux disease	1/66 (1.5%)	1	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Hyperchlorhydria	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Nausea	0/66 (0%)	0	4/65 (6.2%)	4	1/66 (1.5%)	1	0/66 (0%)	0
Toothache	0/66 (0%)	0	2/65 (3.1%)	2	0/66 (0%)	0	1/66 (1.5%)	1
Vomiting	0/66 (0%)	0	1/65 (1.5%)	1	1/66 (1.5%)	1	0/66 (0%)	0
General disorders
Asthenia	0/66 (0%)	0	1/65 (1.5%)	1	1/66 (1.5%)	1	0/66 (0%)	0
Chest pain	1/66 (1.5%)	1	2/65 (3.1%)	3	0/66 (0%)	0	0/66 (0%)	0
Fatigue	0/66 (0%)	0	2/65 (3.1%)	3	1/66 (1.5%)	1	1/66 (1.5%)	2
Oedema peripheral	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	1/66 (1.5%)	1
Pain	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Pyrexia	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Thirst	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Immune system disorders
Food allergy	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Seasonal allergy	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Infections and infestations
Acarodermatitis	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Acute sinusitis	0/66 (0%)	0	1/65 (1.5%)	2	0/66 (0%)	0	1/66 (1.5%)	1
Body tinea	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Bronchitis	1/66 (1.5%)	1	1/65 (1.5%)	1	1/66 (1.5%)	1	1/66 (1.5%)	1
Cellulitis	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Gastroenteritis	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Gastroenteritis viral	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Helicobacter infection	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Hordeolum	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Influenza	0/66 (0%)	0	3/65 (4.6%)	3	1/66 (1.5%)	1	1/66 (1.5%)	1
Laryngitis	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	1/66 (1.5%)	1
Lower respiratory tract infection	0/66 (0%)	0	1/65 (1.5%)	2	0/66 (0%)	0	1/66 (1.5%)	1
Nasopharyngitis	2/66 (3%)	2	3/65 (4.6%)	3	4/66 (6.1%)	4	3/66 (4.5%)	3
Onychomycosis	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Otitis externa	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Otitis media	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Pharyngitis	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Respiratory tract infection	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Sialoadenitis	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Sinusitis	1/66 (1.5%)	1	0/65 (0%)	0	1/66 (1.5%)	1	1/66 (1.5%)	1
Tooth abscess	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Upper respiratory tract infection	1/66 (1.5%)	1	0/65 (0%)	0	1/66 (1.5%)	1	1/66 (1.5%)	1
Viral infection	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	1/66 (1.5%)	1
Injury, poisoning and procedural complications
Arthropod bite	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Contusion	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Meniscus lesion	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Muscle strain	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Wound	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Investigations
Alanine aminotransferase increased	1/66 (1.5%)	1	4/65 (6.2%)	4	7/66 (10.6%)	11	4/66 (6.1%)	4
Aspartate aminotransferase increased	0/66 (0%)	0	2/65 (3.1%)	2	7/66 (10.6%)	9	2/66 (3%)	2
Bilirubin conjugated increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Blood alkaline phosphatase increased	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	2/66 (3%)	2
Blood bilirubin increased	0/66 (0%)	0	0/65 (0%)	0	2/66 (3%)	3	0/66 (0%)	0
Blood glucose increased	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Blood potassium decreased	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Blood triglycerides increased	0/66 (0%)	0	0/65 (0%)	0	2/66 (3%)	2	0/66 (0%)	0
Colonoscopy	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Electrocardiogram qt prolonged	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Free fatty acids increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Gamma-glutamyltransferase increased	0/66 (0%)	0	1/65 (1.5%)	1	3/66 (4.5%)	6	3/66 (4.5%)	3
Hepatic enzyme increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Intermediate density lipoprotein increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Lipase increased	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Liver function test abnormal	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	2/66 (3%)	2
Low density lipoprotein increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Occult blood positive	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Weight decreased	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Weight increased	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
White blood cell count increased	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Metabolism and nutrition disorders
Abnormal loss of weight	0/66 (0%)	0	1/65 (1.5%)	3	1/66 (1.5%)	1	0/66 (0%)	0
Abnormal weight gain	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Decreased appetite	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Hyperglycaemia	1/66 (1.5%)	1	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Hypoglycaemia	1/66 (1.5%)	1	1/65 (1.5%)	1	1/66 (1.5%)	1	0/66 (0%)	0
Increased appetite	1/66 (1.5%)	1	1/65 (1.5%)	1	1/66 (1.5%)	1	0/66 (0%)	0
Vitamin d deficiency	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/66 (0%)	0	4/65 (6.2%)	4	2/66 (3%)	2	1/66 (1.5%)	2
Arthritis	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Back pain	2/66 (3%)	2	2/65 (3.1%)	2	2/66 (3%)	3	1/66 (1.5%)	1
Bursitis	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Flank pain	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Intervertebral disc protrusion	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Muscle spasms	0/66 (0%)	0	1/65 (1.5%)	1	1/66 (1.5%)	1	2/66 (3%)	2
Musculoskeletal chest pain	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Musculoskeletal pain	0/66 (0%)	0	1/65 (1.5%)	4	0/66 (0%)	0	2/66 (3%)	2
Myalgia	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Neck pain	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Pain in extremity	0/66 (0%)	0	2/65 (3.1%)	3	0/66 (0%)	0	1/66 (1.5%)	1
Synovitis	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Nervous system disorders
Carotid arteriosclerosis	1/66 (1.5%)	1	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Cluster headache	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Dizziness	0/66 (0%)	0	0/65 (0%)	0	2/66 (3%)	2	0/66 (0%)	0
Dysgeusia	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Headache	3/66 (4.5%)	3	3/65 (4.6%)	4	4/66 (6.1%)	4	4/66 (6.1%)	5
Hypersomnia	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Hypoaesthesia	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Migraine	1/66 (1.5%)	3	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Paraesthesia	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	2/66 (3%)	2
Radiculopathy	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Sinus headache	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Psychiatric disorders
Depression	1/66 (1.5%)	1	2/65 (3.1%)	4	0/66 (0%)	0	1/66 (1.5%)	1
Insomnia	0/66 (0%)	0	3/65 (4.6%)	3	0/66 (0%)	0	1/66 (1.5%)	1
Panic attack	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Panic disorder	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Renal and urinary disorders
Haematuria	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Renal colic	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchitis chronic	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Chronic obstructive pulmonary disease	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Cough	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	1/66 (1.5%)	1
Epistaxis	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	3/66 (4.5%)	3
Throat irritation	0/66 (0%)	0	1/65 (1.5%)	2	0/66 (0%)	0	2/66 (3%)	2
Skin and subcutaneous tissue disorders
Dermatitis contact	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Eczema	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Hyperhidrosis	1/66 (1.5%)	1	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Pruritus	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Pruritus generalised	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Rash	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0
Swelling face	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Surgical and medical procedures
Dental implantation	0/66 (0%)	0	1/65 (1.5%)	1	0/66 (0%)	0	0/66 (0%)	0
Plastic surgery to the face	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Vascular disorders
Essential hypertension	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Hypertension	2/66 (3%)	2	1/65 (1.5%)	1	0/66 (0%)	0	1/66 (1.5%)	1
Peripheral ischaemia	0/66 (0%)	0	0/65 (0%)	0	1/66 (1.5%)	1	0/66 (0%)	0
Phlebitis	0/66 (0%)	0	0/65 (0%)	0	0/66 (0%)	0	1/66 (1.5%)	1
Venous insufficiency	1/66 (1.5%)	1	0/65 (0%)	0	0/66 (0%)	0	0/66 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.