| 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 | 100000004861 |
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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 is to demonstrate that glycemic control as measured by change in HbA1c from baseline to 26 weeks for LY2605541 is non-inferior compared with insulin glargine when each is combined with preprandial insulin lispro with or without metformin in patients with type 2 diabetes mellitus (T2DM) who have not achieved adequate glycemic control with at least 1 injection of insulin daily with or without OAMs. |
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| E.2.2 | Secondary objectives of the trial |
The gated secondary objectives are to demonstrate that LY2605541 is superior to insulin
glargine (each in combination with preprandial insulin lispro) for:
1. Nocturnal hypoglycemia rate
2. Proportion of patients with HbA1c <7.0% and no nocturnal hypoglycemia
3. HbA1c change from baseline
4. Proportion of patients with HbA1c < 7.0%
5. Fasting serum glucose (FSG) by laboratory measurement
6. Total hypoglycemia rate
The non-gated secondary objectives are to compare the efficacy and safety of LY2605541 versus insulin glargine (each in combination with preprandial insulin lispro) for:
• Total and nocturnal hypoglycemia rates
• Total and nocturnal hypoglycemia incidences
• Proportion of patients with HbA1c ≤6.5%
• FBG (as measured by self-monitored blood glucose [SMBG])
• FBG intra-patient variability (SMBG) as measured by standard deviation (SD)
• Weight change from baseline
• SMBG 9-point profiles
• HbA1c
• Basal, bolus, and total insulin dose (units and units/kg) |
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| 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 |
Protocol Addendum I2R-MC-BIAM (1) - 21-Sep-11
The Impact of LY2605541 versus Insulin Glargine for Patients with Type 2 Diabetes Mellitus Advanced to Multiple Injection Bolus Insulin with Insulin Lispro: a Double-Blind, Randomized, 26 Week Study - The IMAGINE 4 Study: Continuous Glucose Monitoring Addendum
Continuous glucose monitoring (CGM) will be performed in a subpopulation of approximately 148 patients enrolled in study I2R-MC-BIAM.
Pharmacogenetic Evaluations – 15-Sep-11
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 -15-Sep-11
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]Have T2DM based on the World Health Organization (WHO) classification
[2] Are at least 18 years of age
[3] Duration of diabetes ≥1 year
[4] Have an HbA1c value ≥7.0% and <12.0% according to the central laboratory
at screening
[5] BMI ≤45.0 kg/m2
[6] Patients on any glucose lowering regimen that contains at least 1 injection of
insulin per day. Patients will take their last dose of antidiabetic medication with the exception of metformin the day prior to randomization.
[7] This inclusion criterion applies ONLY to women of childbearing potential.
• Are not breastfeeding.
• Test negative for pregnancy at the time of screening and time of randomization based on a serum pregnancy test.
• Do not intend to become pregnant during the study.
• Have practiced a reliable method of birth control (eg, 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).
[8] Have access to a method of communication with the site
[9] Have refrigeration in the home
[10] Capable of, and willing to do the following: adhere to a multiple daily
injection regimen, inject insulin with a covered vial and syringe and prefilled
pen, attend some patient visits in the fasting state, and perform self blood
glucose monitoring and record keeping as required by this protocol, as
determined by the investigator. Caregiver may be responsible for all of the
above.
[11] Have given written informed consent to participate in this study in accordance with local regulations.
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| E.4 | Principal exclusion criteria |
[12] Insulin pump therapy: Continuous subcutaneous insulin infusion therapy prior to screening.
[13] Twice daily insulin glargine: Are using twice daily insulin glargine prior to screening.
[14] Excessive insulin resistance: Defined as having received a daily dose of insulin ≥ 2.0 units/kg at the time of pre-randomization.
[15] Concomitant medications: glucagon-like peptide-1 (GLP-1) receptor agonist (eg, exenatide, exenatide once weekly, or liraglutide), thiazolidinedione (rosiglitazone, pioglitazone), or pramlintide, used concurrently or within 90 days prior to screening.
[16] Lipid-lowering medications: are using niacin preparations as a lipid lowering medication and bile acid
sequestrants within 90 days prior to screening; or, are using lipid-lowering medication at a dose that has not been stable for ≥90 days prior to screening. If a patient has not been on a stable dose of lipid-lowering medication for ≥90 days prior to screening, the site should wait to screen the patient. If the results of the screening laboratory tests require a change to the patient's current lipid-lowering medication or initiation of lipid-lowering medication, it is acceptable to change the lipid-lowering medication for the patient and have the patient return ≥90 days
later to complete some of the screening procedures again.
[17] Triglycerides: Have fasting hypertriglyceridemia (defined as >4.5 mmol/L, >400 mg/dL) at screening, as determined by the central laboratory.
[18] Weight loss medications: Are currently taking, or have taken within the 90 days preceding screening, prescription or over-the-counter medications to promote weight loss.
[19] Severe hypoglycemia history: Have had any episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia) within 6 months prior to entry into the study.
[20] Glycemic control: Have had 2 or more emergency room visits or hospitalizations due to poor glucose control within the 6 months prior to screening.
[21] Diabetic ketoacidosis: Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma requiring hospitalization within 6 months prior to screening.
[22] Cardiovascular: Have cardiac disease with functional status that is New York Heart Association Class III or IV (per New York Heart Association [NYHA] Cardiac Disease Classification).
[23] Renal: Are currently receiving renal dialysis or have a serum creatinine ≥2.0 mg/dL, except for patients taking metformin who will be required to follow local labeling restrictions regarding metformin use and serum creatinine.
[24] Hepatic: 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 ≥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.
[25] 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 are at increased risk for developing cancer or a recurrence of cancer in the opinion of the investigator.
[26] Allergic: Have known or develop hypersensitivity or allergy to any of the study insulins or their excipients.
[27] Hematologic: Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the HbA1c measurement.
[28] Glucocorticoid therapy: Receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, and inhaled preparations) or have received such therapy within 8 weeks immediately before screening with the exception of replacement therapy for adrenal insufficiency.
[29] Diabetic neuropathy: Diagnosed clinically significant diabetic autonomic neuropathy, in the opinion of the investigator.
[30] Transplant: Have had an organ transplant.
[31] Adherence to protocol: Have any other condition (including known drug or alcohol abuse or psychiatric disorder including eating disorder) that precludes the patient from following and completing the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| A change of HbA1c from baseline that is non-inferior to insulin glargine injected once a day each in combination with preprandial insulin lispro with or without metformin |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Nocturnal hypoglycemia rate; proportion of patients with HbA1c <7.0% and no nocturnal hypoglycemia; HbA1c change from baseline; proportion of patients with HbA1c < 7.0%; fasting serum glucose (FSG) by laboratory measurement; total hypoglycemia rate.
Total and nocturnal hypoglycemia rates;
total and nocturnal hypoglycemia incidences; proportion of patients with HbA1c ≤6.5%; FBG (as measured by self-monitored blood glucose [SMBG]); FBG intra-patient variability (SMBG) as measured by standard deviation (SD);
weight change from baseline; SMBG 9-point profiles; HbA1c; basal, bolus, and total insulin dose (units and units/kg).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All gated objective endpoints are at 26 weeks of treatment. Total and nocturnal hypoglycemia rates and incidences have various timepoints such as 0 to 2 weeks, 0 to 12 weeks, 0 to 26 weeks, 2 to 12 weeks, 2 to 26 weeks, 12 to 26 weeks, at 26 weeks for all other objectives. |
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| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
| Australia |
| Austria |
| Brazil |
| Croatia |
| Czech Republic |
| Denmark |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Japan |
| Lithuania |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Slovenia |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
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| 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 |
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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