| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049746 |
| E.1.2 | Term | Insulin-requiring type II diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to demonstrate that LY2605541 is noninferior to insulin glargine for the change in HbA1c from baseline to 52 weeks of treatment in insulin naive patients with T2DM |
|
| E.2.2 | Secondary objectives of the trial |
Gated:
1. Nocturnal hypoglycemia rate during the first 52 weeks of treatment
2. Proportion of patients with HbA1c <7.0% at 52 weeks and no nocturnal hypoglycemia during the first 52 weeks of treatment
3. HbA1c change from baseline after 52 weeks of treatment
4. Proportion of patients with HbA1c <7.0% after 52 weeks of treatment
5. Total hypoglycemia rate during the first 52 weeks of treatment
6. Fasting serum glucose (FSG) by laboratory measurement after 52 weeks of treatment
Non-Gated:
1. Total and nocturnal hypoglycemia rates
2. Total and nocturnal hypoglycemic incidences
3. Weight change from baseline
4. 6-point SMBG profile
5. Proportion of patients with HbA1c <7.0% at 26 and 78 weeks
6. Proportion of patients with HbA1c <7.0% and no nocturnal hypoglycemia at 26 and 78 weeks
7. Triglycerides), total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C)
8. Antibodies to LY2605541 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Continuous Glucose Monitoring Addendum (02 Sep 2011)
In order to better understand the impact of LY2605541 on glucose metabolism as well as within- and between-patient variability, especially during the nocturnal time period, in patients with type 2 diabetes, continuous glucose monitoring (CGM) will be performed in a subpopulation of approximately 189 patients enrolled in study I2R-MC-BIAJ. The primary objective of this addendum is to compare the duration (in minutes) spent with a blood glucose ≤70 mg/dL (in a hypoglycemic state) during the nocturnal period defined as midnight to 06:00 in patients taking LY2605541 versus insulin glargine at 52 weeks.
Pharmacogenetic Evaluations (02 Sep 2011)
Where local regulations allow, a blood sample will be collected for pharmacogenetic analysis. It is a onetime collection, as noted in the Study Schedule. Samples will be stored and analysis may be performed on genetic variants thought to play a role in glucose and insulin regulation, beta cell function, characterization of patients’ responsiveness to LY2605541, or diabetes- related metabolic abnormalities.
Nonpharmacogenetic/Biomarker Evaluation (02 Sep 2011)
Samples will be collected for nonpharmacogenetic biomarker research where local regulations allow. Blood and/or urine samples will be collected at the times specified in the Study Schedule. Samples may be used for research on diabetes progression and/or complications, mechanism of action of LY2605541, patients’ response to LY2605541, in case future analyses are warranted with regard to safety, or in validating diagnostic tools or assay(s) related to diabetes or related metabolic abnormalities or biomarker response to LY2605541.
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| E.3 | Principal inclusion criteria |
[1] T2DM (per World Health Organization [WHO] Classification of Diabetes not treated with insulin
[2] Age 18 years of age or older
[3] Duration of diabetes ≥ 1 year
[4] Have been receiving at least 2 oral anti-hyperglycemic medications (OAMs) for at least 3 months prior to the study. Two or more medications may be contained in one pill. Doses of any OAMs are required to have been stable for the 3 months prior to screening and at least 2 of the OAMs must be dosed at or above half the maximum daily dose allowed by local regulations or the maximally tolerated dose of OAM.
• Note: OAMs must be used in accordance with the corresponding product label. Combination treatments of the OAMs are acceptable if they meet the above criteria. Combination medications should be counted as the number of individual components.
• For Metformin: Where the maximally allowed daily dose of metformin is 2g or greater the metformin (any formulation) must be dosed daily at 1g or greater or at the maximally tolarated dose.
[5] HbA1c of 7.0% to 11.0%, inclusive, according to central lab at screening
[6] BMI ≤ 45 kg/m2
[7] Capable of, and willing to do the following:
• Inject insulin with a vial and syringe and perform self blood glucose monitoring, and
• Record keeping as required by this protocol, as determined by the investigator
Caregiver may do all of the above.
[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 postmenopause) only.
• Are not breastfeeding.
• Test negative for pregnancy at the time of screening based on a urine 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 study drug).
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|
| E.4 | Principal exclusion criteria |
[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] Local OAM restrictions: for patients on OAMs, restrictions for
cardiac, renal, and hepatic diseases, local product regulations must
apply.
[15] 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.
[16] Severe hypoglycemia history: have had any episodes of severe
hypoglycemia within 6 months prior to Visit 1.
[17] 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.
[18] Have cardiac disease with functional status that is New York Heart
Association Class III or IV
[19] Have a history of renal transplantation, or are currently receiving
renal dialysis or have serum creatinine ≥2 mg/dL (177 mol/L).
[20] Have obvious clinical signs or symptoms of liver disease (excluding
non-alcoholic fatty liver disease [NAFLD]), acute or chronic hepatitis,
non alcoholic steatohepatitis (NASH), or elevated liver enzyme
measurements as indicated below:
• total bilirubin ≥2 x the upper limit of normal (ULN) as defined by the
central laboratory, or
• alanine aminotransferase (ALT)/(serum glutamic pyruvic
transaminase (SGPT) >2.5 x ULN as defined by the central laboratory, or
• aspartate aminotransferase (AST)/(serum glutamic oxaloacetic
transaminase (SGOT) >2.5 x ULN as defined by the central laboratory.
[21] 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.
[22] Have 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.
[23] Have known hypersensitivity or allergy to any of the study insulins
or their excipients.
[24] 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.
[25] Have fasting triglycerides >400 mg/dL (>4.5 mmol/L) at Visit 1 as
determined by the central laboratory.
[26] Have irregular sleep/wake cycle (for example, patients who sleep
during the day and work during the night) in the investigator's opinion.
[27] Have any other conditions (including known drug or alcohol abuse
or psychiatric disorder) that preclude the patient from following and
completing the protocol.
[28] Are Lilly employees or Lilly representatives (including employees,
temporary contract workers, or designees responsible for the conduct of
the study) or Boehringer Ingelheim employees.
[29] 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.
[30] Have been treated with a drug within the last 30 days that has not
received regulatory approval at the time of study entry.
[31] Are currently enrolled in, or discontinued within the last 30 days
from, a clinical trial involving an investigational product or nonapproved
use of a drug or device other than LY2605541, or concurrently enrolled
in any other type of medical research judged not to be scientifically or
medically compatible with this study.
[32] 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.
[33] 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.
[39] Lipid-lowering medications:
• are using niacin preparations as a lipid-lowering medication and 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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| A change of HbA1c from baseline to 52 weeks that is not inferior to glargine. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Nocturnal and total hypoglycemia rates and incidences superior to
glargine, proportion of patients with HbA1c <7% at 52 weeks of
treatment (also HbA1c <7% with no nocturnal hypoglycemia, FPG by
laboratory, FBG by SMBG, weight change from baseline, SMBG 6-pt
profile, HbA1c, insulin dose, number of dose adjustments to steady
state, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol,
insulin and insulin analog antibodies, other safety endpoints such as
serious adverse events, vitals, treatment-emergent adverse events,
Health Outcomes measurements EQ-5D, ITSQ, and LBSS. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All gated objective endpoints are at 52 weeks of treatment. Many of the
non-gated secondary endpoints have various timepoints such as 0 to 12
weeks, 0 to 26 weeks, 0 to 78 weeks, 12 to 26 weeks, 26 to 52 weeks,
52 to 78 weeks for nocturnal and total hypoglycemia incidences; 0 to 12 weeks, 0 to 26 weeks, 0 to 52 weeks, 0 to 78 weeks, 12 to 26 weeks, 26
to 52 weeks, 52 to 78 weeks for nocturnal and total hypoglycemia rates;
26 and 78 weeks for FPG by laboratory, 26 and 78 weeks for proportion
of patients with HbA1c <7%, and the same as immediately above with
no nocturnal hypoglycemia, and HbA1c change from baseline |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Czech Republic |
| Finland |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Lithuania |
| Mexico |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| last visit of the last subject undergoing the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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