| 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 | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045228 |
| E.1.2 | Term | Type I 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 of this study is to demonstrate that glycemic control as measured by HbA1c at 26 weeks for LY2605541 is non-inferior to insulin glargine when each is combined with pre-prandial insulin lispro in patients with type 1 diabetes mellitus. |
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| E.2.2 | Secondary objectives of the trial |
Gated: To demonstrate that LY2605541 is superior to insulin glargine (both in combination with pre-prandial insulin lispro) at 26 weeks for:
1.Nocturnal hypoglycemia rate.
2.HbA1c
3.Proportion of patients with HbA1c <7.0%
4.FSG by laboratory measurement
5.Total hypoglycemia rate.
Non-gated: To compare the efficacy and safety of LY2605541 versus insulin glargine (both in combination with pre-prandial insulin lispro) treatment groups for:
1.Total and nocturnal hypoglycemia rates and incidences
2.Weight change from baseline
3.SMBG 9-point profiles
4.Proportion of patients with HbA1c <7.0% and ≤6.5%
5.Proportion of patients with HbA1c <7.0% without nocturnal hypoglycemia
7.HbA1c change from baseline
8.HbA1c at 52 and 78 weeks
9.Basal, mealtime, and total insulin dose (units and units/kg)
10.Triglycerides (log transformation prior to analysis), total cholesterol, LDL-cholesterol, HDL-cholesterol
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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 |
BIAN addendum 1.1: Effect of LY2605541 on hepatic fat content, visceral adipose tissue and lipid parameters in comparison to Insulin Glargine (11-Aug-2011, original version; 15-Sep-2011, amended version)
The primary objective is to compare LY2605541 versus insulin glargine therapy each in combination with preprandial insulin lispro for the change from baseline of percentage liver fat content (LFC) as measured by magnetic resonance imaging (MRI) after 26 weeks in patients with type 1 diabetes mellitus.
BIAN addendum 2.1: Effect of LY2605541 on lipid parameters in comparison to Insulin Glargine (11-Aug-2011, original version; 15-Sep-2001, amended version)
The primary objective is to compare LY2605541 versus insulin glargine each in combination with preprandial insulin lispro for the change from baseline of plasma low-density lipoprotein (LDL) particle concentration (nmol/l) by using nuclear magnetic resonance (NMR) after 26 weeks in patients with type 1 diabetes mellitus who have participated in either Protocol I2R-MC-BIAN Addendum (1) or Protocol I2R-MC-BIAN(2). |
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| E.3 | Principal inclusion criteria |
[1] Have had T1DM 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 < 12% according to the central laboratory at screening
[5] Body mass index ≤ 35.0 kg/m2
[6] Have been treated for at least 90 days prior to screening with insulin (glargine, NPH, or detemir) in combination with pre-meal insulin, or self mixed or pre-mixed insulin regimens with any basal and bolus insulin combination administered at least twice daily, or continuous subcutaneous insulin infusion therapy
[7] Female patients who are not breastfeeding, test negative for pregnancy at the time of screening and enrollment based on a serum pregnancy test, intend not to become pregnant during the study and have practiced a reliable method of birth control (for example, use of oral contraceptives or levonorgestrel; diaphragms with contraceptive jelly; cervical cap 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 and for 2 weeks following the last dose of study drug.
[8] Have access to a telephone
[9] Have refrigeration in the home
[10] Capable of, willing and desirous to do the following: adhere to a multiple daily injection regimen, inject insulin with a prefilled pen 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.
[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] Are using twice daily insulin glargine having been inadequately controlled on single daily dosed glargine prior to screening.
[13] Excessive insulin resistance defined as having received a total daily dose of insulin > 1.5 U/kg at the time of randomization.
[14] Receiving any oral or injectable medication (other than metformin for treatment of polycystic ovarian disease) intended for the treatment of diabetes mellitus other than insulins in the 90 days prior to screening. Note: for subjects on metformin, the following exclusion criteria will apply: have serum creatinine concentration that contraindicates metformin use per the country-specific product labeling;
[15] Lipid-lowering medications: are using niacin preparations as a lipid-lowering medication and/or 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 the 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 for the patient and have the patient return ≥ 90 days later to complete some of the screening procedures again.
[16] Have fasting hypertriglyceridemia (defined as >4.5 mmol/L, <400 mg/dl) at screening, as determined by the central laboratory.
[17] Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia as determined by the investigator) within 6 months prior to entry into the study.
[18] Have had 2 or more emergency room visits or hospitalizations due to poor glucose control (hyperglycemia or DKA) 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 Heart Association [NYHA] Cardiac Disease Classification).
[20] Renal: have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine > 2.5 mg/dL.
[21] 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 of: total bilirubin (≥2 x ULN), 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) > 2.5 x ULN as defined by the central laboratory.
[22] 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.
[23] Allergy: have known hypersensitivity or allergy to any of the study insulins or their excipients.
[24] 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.
[25] 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.
[26] Diagnosed clinically significant diabetic autonomic neuropathy, in the opinion of the investigator.
[27] 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 to 26 weeks that is not inferior to glargine when each is combined with pre-prandial insulin lispro. |
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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; HbA1c; proportion of patients with HbA1c <7.0%; FSG (laboratory measurement); total hypoglycemia rate; total and nocturnal hypoglycemia rates and incidences; weight change from baseline, SMBG 9-point profiles; proportion of patients with HbA1c <7.0%; proportion of patients with HbA1c ≤ 6.5%, proportion of patients with HbA1c < 7.0% without nocturnal hypoglycemia; HbA1c change from baseline; HbA1c at 52 and 78 weeks; basal, bolus, and total insulin doses (units and units/kg); triglycerides (log transformation prior to analysis), total cholesterol, LDL-C, HDL-C; antibodies to LY2605541; FSG by laboratory; FBG (as measured by SMBG), FBG intra-patient variability (as measured by SMBG); 0300-hour BG to fasting BG excursion; ITSQ; LBSS; EQ-5D; RAPA; additional safety endpoints (treatment-emergent adverse events [TEAEs], SAEs, vital signs, treatment exposure, other laboratory measures, etc.) |
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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. Nocturnal and total hypoglycemia rates and incidences have various timepoints such as 0 to 2 weeks, 0 to 12 weeks, 0 to 26 weeks, 0 to 52 weeks, 0 to 78 weeks, 2 to 12 weeks, 2 to 26 weeks, 12 to 26 weeks, 12 to 52 weeks, 12 to 78 weeks, 26 to 52 weeks, 52 to 78 weeks; at 52 and 78 weeks for proportion of patients with HbA1c <7.0%, HbA1c and FSG by laboratory; at 26 weeks for ITSQ and EQ-5D, at 26 and 78 weeks for RAPA, and at 26, 52 and 78 weeks for all the 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| 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 | 31 |
| 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 |
| France |
| Italy |
| Japan |
| Austria |
| Germany |
| Mexico |
| Poland |
| Russian Federation |
| 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
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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