Type II DM

Objectives: The primary objective of this study is to demonstrate that LY2605541 is non-inferior to insulin glargine for the change in hemoglobin A1c (HbA1c) from baseline to 26 weeks of treatment in Asian insulin-naïve patients with T2DM using a non-inferiority margin (NIM) of 0.4%. The secondary objective of the study is to compare the efficacy and safety of LY2605541 versus insulin glargine treatment groups for the following parameters after 26 weeks (unless otherwise stated):  Total hypoglycemia rates (0 to 12, 0 to 26, and 12 to 26 weeks)  Nocturnal hypoglycemia rates (0 to 12, 0 to 26, and 12 to 26 weeks)  Total and nocturnal hypoglycemic incidences (0 to 12, 0 to 26, and 12 to 26 weeks)  Fasting serum glucose (FSG) by laboratory for time points (4, 8, 12, and 16 weeks)  Fasting blood glucose (FBG) (by self-monitoring blood glucose [SMBG])  FBG intra-patient variability (by SMBG)  Weight change from baseline  SMBG 9-point profile (pre-morning meal [fasting], 2 hours post morning meal, pre-midday meal, 2 hours post midday meal, pre-evening meal, 2 hours post evening meal, bedtime, 0300 hours, and fasting the subsequent morning [next day]).  Proportion of patients with HbA1c 6.5%  HbA1c change from baseline (12 weeks)  HbA1c  Insulin dose (U and U/kg)  Time to steady state for basal insulin (stable maximum dose)  Triglycerides, total cholesterol, LDL-C, and HDL-C  Anti-LY2605541 antibody  Health State Utility (EuroQol 5-Dimension [EQ-5D] questionnaire)  Treatment satisfaction (Insulin Treatment Satisfaction Questionnaire [ITSQ])  Low Blood Sugar Survey (LBSS)

(LY2605541)

(LY2605541)

solution

100U/ml

Primary Efficacy Measure
The primary efficacy measure is the change in HbA1c from baseline to 26 weeks
Secondary Efficacy Measures
The following secondary efficacy measures will be collected at the times shown in the Study
Schedule (Attachment 1).
 Hypoglycemia (total and nocturnal rate and proportion of patients experiencing at least
1 event for each hypoglycemia category) by visit, and during the following periods: 0 to
12 weeks, 12 to 26 weeks, and 0 to 26 weeks.
 Proportion of patients with HbA1c 6.5% and <7.0% and endpoint at Week 26.
 Proportion of patients with HbA1c <7.0% at Week 26 without nocturnal hypoglycemia
event from 0 to 26 weeks.
 FSG (laboratory measurements) and FBG change by visit.
 Intra-patient variability, as measured by the standard deviation (SD) of the FBG (by
SMBG) by visit.
 SMBG 9-point profile (pre-morning meal [fasting], 2 hours post morning meal,
pre-midday meal, 2 hours post midday meal, pre-evening meal, 2 hours post evening
meal, bedtime, 0300 hours, and fasting the subsequent morning [next day]) by visit.
 Body weight change from baseline by visit.
 HbA1c change from baseline to each post baseline visit.
 HbA1c at each visit.
 Insulin dose by visit (U and U/kg).
 Time to steady state. Steady state is defined as the first local maximum dose in the
window of 2 to +2 weeks, which means the local maximum dose is the peak dose value
among all of doses from 2 weeks prior to it to 2 weeks after it.

[1] Have T2DM (per World Health Organization [WHO] Classification of
Diabetes) not treated with insulin.
[2] Are 20 years of age or older (local laws must be followed where an older
minimum age is stipulated)
[3] Have had diabetes for at least 1 year
[4] Have been receiving at least two OAMs for at least 3 months prior to Visit 1.
Two or more medications may be contained in 1 pill. Doses of at least
two OAMs should be  the minimum daily doses and  the approved maximum
doses by local regulations (Table BIAQ.0.1). Doses of any OAMs are
required to have been stable for at least 3 months prior to Visit 1.
[5] Have HbA1c of 7.0% to 11.0%, inclusive, according to central laboratory at
Visit 1
[6] BMI 35.0 kg/m2
[7] Are capable of, and willing to do the following:
 Inject insulin with a pre-filled insulin pen and perform SMBG (Daily FBG
measurement and 9-point SMBG at Visit 3, Visit 4, Visit 7, Visit 11,
Visit 13, and Visit 16)
 Record keeping as required by this protocol, as determined by the
investigator
[8] Have given written informed consent to participate in this study in accordance
with local regulations
[9] Have access to a telephone
[10] Have refrigeration in the home
[11] This inclusion criterion applies to females of child-bearing potential (not
surgically sterilized and between menarche and 1-year postmenopausal) only;
 Are not breastfeeding.
 Test negative for pregnancy at the time of screening (Visit 1) based on a
serum pregnancy test.
 Intend not to become pregnant during the study.
 Have practiced a reliable method of birth control (for example, use of oral
contraceptives or levonorgestrel; diaphragms with contraceptive jelly;
cervical caps with contraceptive jelly; condoms with contraceptive foam;
intrauterine devices; partner with vasectomy; or abstinence) for at least
6 weeks prior to screening.
 Agree to continue to use a reliable method of birth control during the study,
as determined by the investigator (and for 2 weeks following the last dose of
investigational product).

[12] Insulin therapy: have used insulin therapy (outside of pregnancy) anytime in
the past 2 years, except for short term treatment of acute conditions, and up to a
maximum of 4 continuous weeks. Insulin use of any duration during
pregnancy is not considered an exclusion criterion.
[13] Concomitant medications: rosiglitazone, pramlintide, glucagon-like peptide-1
(GLP-1) receptor agonist (for example, exenatide, exenatide once weekly or
liraglutide) used concurrently or within 3 months prior to Visit 1 (screening).
[14] Lipid-lowering medications:
are using niacin preparations as a lipid-lowering medication and/or bile acid
sequestrants within 90 days prior to Visit 1; or,
are using lipid-lowering medication at a dose that has not been stable for 90
days prior to Visit 1.
[15] Local OAM restrictions: for patients on OAMs, restrictions for cardiac, renal
and hepatic diseases, local product regulations must apply.
[16] Weight loss medications: are currently taking, or have taken within the
3 months preceding Visit 1, prescription or over-the-counter medications to
promote weight loss.
[17] Severe hypoglycemia history: have had any episodes of severe hypoglycemia
(as outlined in Section Error! Reference source not found.) within 6 months
prior to Visit 1.
[18] Diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar nonketotic coma
(HHNKC): have had 1 or more episodes of ketoacidosis or hyperosmolar
state/coma in the past 6 months
[19] Cardiovascular: have cardiac disease with functional status that is New York
Heart Association Class III or IV (per New York Hearth Association [NYHA]
Cardiac Disease Classification; Error! Reference source not found.)
[20] Renal: have a history of renal transplantation, or are currently receiving renal
dialysis or have serum creatinine 2.0 mg/dL (177 mol/L). Patients taking
metformin should not exceed the creatinine level specified in the local label.
[21] Hepatic: have obvious clinical signs or symptoms of liver disease (excluding
non-alcoholic fatty liver disease [NAFLD]), acute or any chronic hepatitis,
non-alcoholic steatohepatitis (NASH), or elevated liver enzyme measurements
as indicated below:
total bilirubin 2x the upper limit of normal (ULN) as defined by the central
laboratory, or
alanine aminotransferase (ALT)/(serum glutamic pyruvic transaminase (SGPT)
>2.5x ULN as defined by the central laboratory, or
aspartate aminotransferase (AST)/(serum glutamic oxaloacetic transaminase
(SGOT) >2.5x ULN as defined by the central laboratory.
[22] Hematologic: have had a blood transfusion or severe blood loss within
3 months prior to Visit 1 or have known hemoglobinopathy, hemolytic anemia
or sickle cell anemia, or any other traits of hemoglobin abnormalities known to
interfere with the measurement of HbA1c.
[23] Malignancy: have active or untreated malignancy, have been in remission
from clinically significant malignancy (other than basal cell or squamous cell
skin cancer) for less than 5 years, or at increased risk for developing cancer or a
recurrence of cancer in the opinion of the investigator.
[24] Allergy: have known hypersensitivity or allergy to any of LY2605541 and
insulin glargine or their excipients.
[25] Surgical operation: have undergone a major surgical operation within 3 months
prior to Visit 1, or plan to undergo a major surgical operation requiring
hospitalization for at least 1 day during the course of the clinical trial.
[26] Retinopathy and maculopathy: have pre-proliferative and proliferative
retinopathy, maculopathy requiring treatment or not clinically stable in the last 6
months, or patients with active changes in subjective eye symptoms as
determined by the investigator if an eye exam has not been performed in the last
6 months.
[27] Glucocorticoid therapy: are receiving chronic (lasting longer than
14 consecutive days) systemic glucocorticoid therapy (excluding topical,
intranasal, intraocular, and inhaled preparations) or have received such therapy
within the 8 weeks immediately preceding Visit 1.
[28] Triglycerides: have fasting triglycerides >400 mg/dL (4.5 mmol/L) at Visit 1
as determined by the central laboratory.
[29] Sleep cycle: have irregular sleep/wake cycle (for example, patients who sleep
during the day and work during the night) in the investigator’s opinion.
[30] Adherence to protocol: have any other conditions (including known drug or
alcohol abuse or psychiatric disorder) that precludes the patient from following
and completing the protocol.
[31] Lilly employees: are Lilly employees or are Lilly representatives (including
employees, temporary contract workers, or designees responsible for the
conduct of the study).
[32] Site personnel: are investigator site personnel directly affiliated with this study
and/or their immediate families. Immediate family is defined as a spouse,
parent, child, or sibling, whether biological or legally adopted.
[33] Non-approved drug: have been treated with a drug within the last 30 days that
has not received regulatory approval at the time of study entry.
[34] Other study participation: are currently enrolled in a clinical trial involving an
investigational product or nonapproved use of a drug or device (other than the
investigational product used in this study), or concurrently enrolled in any other
type of medical research judged not to be scientifically or medically compatible
with this study.
[35] Prior study participation: have participated, within the last 30 days from a
clinical trial involving an investigational product other than the investigational
product used in this study. If the previous investigational product has a long
half-life, 3 months or 5 half-lives (whichever is longer) should have passed.
[36] Prior study with LY2605541: have previously completed or withdrawn from
this study after having signed informed consent or any other study investigating
LY2605541 after receiving at least 1 dose of investigational product.
[37] General restrictions: are unable and/or unwilling to provide informed consent,
make themselves available for the duration of the study, or abide by study
procedures and restrictions.