| 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 |
| To demonstrate that glycemic control as measured by HbA1c at 52 weeks for LY2605541 is non-inferior compared with insulin glargine when each is combined with pre-prandial insulin lispro in patients with T1DM. |
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| E.2.2 | Secondary objectives of the trial |
Gated:To demonstrate that LY2605541 is superior to insulin glargine (each in combination with pre-prandial insulin lispro) for:
• Nocturnal hypoglycemia rate
• HbA1c
• Proportion of patients with HbA1c <7.0%
• Fasting serum glucose (FSG) by laboratory measurement
• Total hypoglycemia rate
Non-Gated: To compare the efficacy and safety of LY2605541 versus insulin glargine (each in combination with pre-prandial insulin lispro):
• Total and nocturnal hypoglycemia rates and incidence
• Weight change
• SMBG 9-point profiles
• Proportion of patients with HbA1c <7.0% and HbA1c ≤ 6.5%
• Proportion of patients with HbA1c <7% without nocturnal hypoglycemia
• HbA1c change from baseline
• HbA1c endpoint
• Basal, mealtime, and total insulin dose
•Triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol
• Antibodies to LY2605541
• Additional safety endpoints
• FSG by laboratory
• FBG (measured by SMBG)
• FBG (SMBG) intra-subject variability |
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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 |
Pharmacogenetic Evaluations (10 September 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 (10 September 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] Have T1DM based on the World Health Organization (WHO) classification
[2] Are at least 18 years of age
[3] Have had diabetes for at least 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 detemir, insulin glargine, or NPH insulin 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] This inclusion criterion applies to all females only.
• Are not breastfeeding.
• Test negative for pregnancy at the time of screening and time of randomization 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 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 vial and syringe and prefilled pen and perform self blood glucose monitoring and record keeping as required by this protocol. 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 insulins or 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 medication: are using niacin preparations as lipid lowering medication 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 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.
[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) within 6 months prior to screening.
[18] Have had 2 or more emergency room visits or hospitalizations due to poor glucose control (hyperglycemia or diabetic ketoacidosis [DKA]) within 6 months prior to screening.
[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), 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
• ALT/serum glutamic pyruvic transaminase (SGPT) >2.5 x ULN as defined by the central laboratory, or
• 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 or develop 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 52 weeks that is not inferior to glargine when 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) |
| Total and nocturnal hypoglycemia rates and incidence; weight change from baseline by visit; SMBG 9-pt profiles; proportion of patients with HbA1c <7.0% without nocturnal hypoglycemia; HbA1c change from baseline; proportion of patients with HbA1c <7%; proportion of patients with HbA1c ≤6.5%; HbA1c endpoint by visit; basal, mealtime, and total insulin dose by visit; triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol; antibodies to LY2600541; additional safety endpoints (treatment-emergent adverse events, serious adverse events, vital signs, treatment exposure, other laboratory measures, etc); FSG by laboratory, FBG (measured by SMBG), FBG (SMBG) intra-subject patient variability, 0300-hour BG to fasting FBG excursion, ITSQ, LBSS, EQ-5D, and RAPA. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All gated objective endpoints are at 52 weeks of treatment. Nocturnal and total hypoglycemia rates and incidence have various timepoints such as 0-2 weeks, 0-12 weeks, 0-26 weeks, 0-52 weeks, 2-12 weeks, 2-26 weeks, 12-26 weeks, 26-52 weeks; proportion of patients with HbA1c <7.0%, HbA1c, and FSG by laboratory at 26 weeks; ITSQ and EQ-5D at 52 weeks; all other endpoints at 26 and 52 weeks. |
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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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Greece |
| Ireland |
| Croatia |
| Netherlands |
| New Zealand |
| Slovakia |
| Sweden |
| Australia |
| Brazil |
| Lithuania |
| Spain |
| Israel |
| Poland |
| Slovenia |
| South Africa |
| 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
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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