| 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 is to demonstrate that LY2605541 is noninferior to insulin glargine for the change in HbA1c from baseline to 26 weeks of treatment in patients with T2DM treated with basal insulin alone or in combination with oral antihyperglycemic medication(s) (OAMs) |
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| E.2.2 | Secondary objectives of the trial |
The secondary gated objectives are to demonstrate that LY2605541 is superior to insulin glargine (at 26 weeks) 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. Total hypoglycemia rate
6. Fasting serum glucose (FSG) by laboratory
The secondary non-gated objectives are to compare the efficacy and safety of LY2605541 vs insulin glargine for the following objectives:
• All of the above at other timepoints
AND
• Total and nocturnal hypoglycemic incidences
• FBG (by self-monitored blood glucose [SMBG])
• FBG intra-patient variability by SMBG
• Weight change from baseline
• 6-point SMBG profile
• Proportion of patients with HbA1c ≤6.5%
• HbA1c
• Insulin dose
• Number of dose adjustments to steady-state
• Triglycerides, total cholesterol, LDL C, HDL-C
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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-BIDJ(1) 9 Feb. 2012
Effect of LY2605541 on Hepatic Fat Content, Visceral Adipose Tissue, and Lipid Parameters in Comparison to Insulin Glargine
The primary objective is to compare LY2605541 vs insulin glargine for the change from baseline of percentage liver fat content (LFC), as measured by MRI at 26 weeks.
The secondary objectives are to compare LY2605541 versus insulin glargine at 26 and 52 weeks for:
• Hepatic fat and body composition measured by MRI
• Lipoprotein measured by Nuclear Magnetic Resonance (NMR)
• Additional laboratory measurements
Protocol Addendum I2R-MC-BIDJ(2) – 28-Jan. 2012
Effect of LY2605541 on Lipid Parameters in Comparison to Insulin Glargine
The primary objective is to compare LY2605541 vs insulin glargine for the change from baseline of serum LDL particle concentration (nmol/L) by using nuclear magnetic resonance (NMR) at 26 weeks.
The secondary objectives are to compare LY2605541 versus insulin glargine at 26 and 52 weeks for:
• Lipoprotein measured by NMR
• Additional laboratory measurements
Pharmacogenetic Evaluations – 16 Jan. 2012
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 – 16 Jan. 2012
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 (per World Health Organization [WHO] Classification of Diabetes)
[2] Are 18 years of age or older
[3] Have had diabetes for at least 1 year
[4] Have been receiving basal insulin (NPH [isophane], insulin detemir or insulin glargine) and from 0 to 3 OAMs for at least 90 days prior to the study. Doses of any OAMs are required to have been stable for ≥90 days prior to screening and at least 1 of the OAMs must be dosed at, or above, half the maximum daily dose allowed by local regulations or at the maximally tolerated dose.
• Note: OAMs must be used in accordance with the corresponding product label at the time of screening. Combination treatments of the OAMs are acceptable if they meet the above criteria. Combination medications should be counted as the number of individual components.
[5] Have HbA1c ≤9.0% according to central lab at screening
[6] Have BMI ≤45.0 kg/m2
[7] Are capable of, and willing to do, the following, as determined by the investigator:
• Inject insulin with a prefilled pen and perform self blood glucose monitoring, and
• Record keeping as required by this protocol.
Caregiver may be responsible for all of the above.
[8] This inclusion criterion applies to females of childbearing potential (not surgically sterilized and between menarche and 1-year postmenopausal) only:
• Are not breastfeeding;
• Test negative for pregnancy at the time of screening and 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).
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| E.4 | Principal exclusion criteria |
[12] Insulin therapy: have used a routine regimen of insulin glargine twice daily in the past 90 days or have used routine, prandial (rapid-acting) insulin therapy (outside of pregnancy) anytime in the past 6 months, except for short-term treatment of acute conditions, and up to a maximum of 4 continuous weeks. Insulin use of any type or 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 90 days prior to screening.
[14] Local OAM restrictions: for patients on OAMs, restrictions for cardiac, renal, and hepatic diseases in the local product regulations must apply.
[15] 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.
[16] Severe hypoglycemia history: have had any episodes of severe hypoglycemia within 6 months prior to screening.
[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] 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)
[19] Renal: have a history of renal transplantation, or are currently receiving renal dialysis or have serum creatinine ≥2 mg/dL (177 mol/L).
[20] 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 ≥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] 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 measurement of HbA1c.
[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] 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 screening.
[25] Triglycerides: have fasting triglycerides >400 mg/dL (>4.5 mmol/L) at screening as determined by the central laboratory.
[26] 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.
[27] Adherence to protocol: have any other conditions (including known drug or alcohol abuse or psychiatric disorder) that preclude the patient from following and completing the protocol.
[28] Lipid-lowering medications:
• are using or have used niacin preparations as a lipid-lowering medication and/or bile acid sequestrants within 90 days prior to screening; or,
• are using or have used lipid-lowering medication at a dose that has not been stable for ≥90 days prior to screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in HbA1c from baseline |
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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 rate; proportion of patients with at least 1 hypoglycemia event for each hypoglycemia category; proportion of patients with HbA1c ≤6.5% and <7.0%; proportion of patients with HbA1c <7.0% without nocturnal hypoglycemia; FSG (laboratory measurements); FBG (by SMBG); FBG intra patient variability (SMBG), as measured by standard deviation; SMBG 6-point profile; weight change from baseline; HbA1c actual and change from baseline; insulin dose; number of dose adjustments to steady-state |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 26 weeks: all gated objective endpoints
- 0 to 12 weeks, 12 to 26 weeks, 0 to 26 weeks, 26 to 52 weeks, 0 to 52 weeks, and by visit: total and nocturnal hypoglycemia rate and proportion of patients with at least 1 hypoglycemia event for each hypoglycemia category
- 26 and 52 weeks: proportion of patients with HbA1c ≤6.5% and <7.0%; proportion of patients with HbA1c <7.0% without nocturnal hypoglycemia
- By visit: FSG (laboratory measurements); FBG (by SMBG); FBG intra patient variability (SMBG), as measured by standard deviation; SMBG 6-point profile; weight change from baseline; HbA1c actual and change from baseline; insulin dose
- number of dose adjustments to steady-state
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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 | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Czech Republic |
| Germany |
| Greece |
| Israel |
| Romania |
| Russian Federation |
| Spain |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 26 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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