| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063624 |
| E.1.2 | Term | Type II diabetes mellitus inadequate control |
|
| 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 test the hypothesis that glycemic control achieved when initiating insulin treatment with insulin lispro mid mix /low mix as a single daily injection either before midday or evening meal, and progressing up to three daily injections of mid mix/low mix is noninferior to that achieved when initiating insulin glargine as a single daily injection and progressing to up to three additional daily injections of meal-time insulin lispro.
Glycemic control will be determined by measuring the mean change from baseline to endpoint of hemoglobin A1c (HbA1c) after approximately 48 weeks, in patients with type 2 diabetes mellitus who have a habit of consuming less than 15% of their daily caloric intake at morning meal and who have inadequate glycemic control (HbA1c ≥7%) on oral antihyperglycemic medication(s). A noninferiority margin of 0.4% for HbA1c will be used.
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| E.2.2 | Secondary objectives of the trial |
To report the % of patients at endpoint using each of possible final insulin regimens. Additional secondary objectives are to compare effects of the 2 treatment regimens, with respect to
•mean HbA1c-change (16, 32, 48 weeks)
•percentages of patients achieving HbA1c ≤6.5%and<7% (16, 32, 48 weeks)
•7-point self-monitored blood glucose (SMBG) profiles at baseline, 16, 32, 48 weeks
•mean change from baseline in postprandial blood glucose, 16, 32, 48 weeks
•mean change from baseline to endpoint in lipid + cholesterol profiles
•mean daily total, basal and prandial insulin dose at 16, 32, 48 weeks
•body weight change from baseline to endpoint
•change of dietary pattern
•safety, as measured by the incidence and rate of self-reported hypoglycemic episodes, including all, severe, daytime and nocturnal hypoglycemia
•incidence of treatment-emergent adverse events |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] Present with type 2 diabetes mellitus, based on a history and clinical impression that is consistent with the World Health Organization [WHO] Classification of Diabetes (see Protocol Attachment S020.3).
[2] Patients are ≥30 years of age and <75 years of age.
[3] Have been receiving oral antihyperglycemic medications (OAMs) including metformin, without insulin for at least 90 days immediately prior to the study (Visit 1). The OAMs should include at least two of the following (one of which must be metformin) at maximally tolerated doses, AND meet the additional dosing criteria shown:
Metformin, Minimum Dose: 1500 mg/day
Sulfonylurea (SU) Minimum Dose: half the maximum daily dose, according to the licence in the participating country.
Thiazolidinedione (TZD) Minimum Dose: 30 mg/day pioglitazone, OR
4 mg/day rosiglitazone
NOTE: The OAMs also must be used in accordance with the product label and be approved for use with insulin in the patient’s country (see Exclusion Criterion [8]).
NOTE: Combination treatments of the OAMs above are acceptable if they meet the criteria above. For example, Avandamet® (rosiglitazone maleate and metformin hydrochloride) would cover the categories of a TZD and metformin.
[4] Have a hemoglobin A1c (HbA1c) ≥7.0% and <11.0% as measured at Visit 1.
[5] Routinely consume less than 15% of their daily caloric intake at breakfast (defined as a meal consumed between 5 am and 10 am) as determined based on the history and a 1-day dietary recall.
[6] As determined by the investigator, are capable and willing to do the following:
• use the insulin injection device according to the instructions provided;
• inject insulin while continuing to use the prestudy regimen of OAMs specified in Inclusion Criterion [3];
• perform self monitoring of blood glucose (SMBG) to adjust insulin doses, and to provide 7-point SMBG profiles before principal study visits;
• use the patient diary as required for this protocol;
• be receptive to diabetes education (as per routine practice), including following dietary and lifestyle advice as appropriate;
• comply with the required study visits and be willing to receive regular telephone calls between visits.
[7] Have given written informed consent to participate in this study in accordance with local regulations. |
|
| E.4 | Principal exclusion criteria |
[8] Are taking a TZD dose greater than what is indicated in combination with insulin according to the TZD label in their respective country.
NOTE: In countries where the combination of a TZD and insulin is contraindicated, patients taking a TZD must have been on a prestudy regimen of three OAMs in Inclusion Criteria [3], and must discontinue the TZD at Visit 1.
[9] Are taking any other glucose-lowering agents (such as meglitinide, alpha-glucosidase inhibitors, DPP-lV inhibitors, etc.) not mentioned in Inclusion Criterion [3].
[10] Have taken acarbose, miglitol, pramlintide, exenatide, repaglinide, or nateglinide in the past 6 weeks, or for a total of 30 days or more, in the last 24 weeks.
[11] Have a body mass index greater than 40 kg/m2.
[12] Have had more than one episode of severe hypoglycemia (within 24 weeks prior to entry into the study (Visit 1).
[13] Are pregnant or intend to become pregnant during the course of the study, or are sexually active women of childbearing potential not actively practicing birth control by a method determined by the investigator to be medically acceptable.
[14] Are women who are breastfeeding.
[15] Have cardiac disease with a functional status that is Class III or IV (see Protocol Attachment S020.4); or, if taking a TZD, have cardiac disease of a less severe functional status, which would contraindicate in their respective country the use of TZD alone or in combination with insulin.
[16] Have a history of renal transplantation, or are currently receiving renal dialysis.
[17] Have obvious clinical signs or symptoms, or laboratory evidence, of liver disease (alanine transaminase [ALT] OR aspartate transaminase [AST] greater than 2.5 times the upper limit of the reference range).
[18] Are undergoing therapy for a malignancy, other than basal-cell or squamous-cell skin cancer.
[19] Have known hypersensitivity or allergy to any of the study insulins or excipients of the study insulins.
[20] 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.
[21] Have received systemic glucocorticoid therapy within the 3 months prior to Visit 1.
NOTE: Topical preparations, nasal preparations, intra-articular administration, as well as physiologic replacement for Addison’s disease and hypopituitarism are permitted.
[22] Have an irregular sleep/wake cycle (for example, patients who sleep during the day and work during the night).
[23] Have any other condition (including known drug or alcohol abuse or psychiatric disorder) that precludes the patient from following and completing the protocol.
[24] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
[25] 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.
[26] Are Lilly employees.
[27] Have a serum creatinine concentration that contraindicates use of metformin according to the country-specific metformin product label.
[28] Have known metabolic or lactic acidosis.
[29] Have any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis.
[30] Have had a radiologic contrast study within 48 hours prior to entry in the study (Visit 1) or plan to have such a procedure or surgery performed during the study.
[31] During the period between Visits 1 and 2, had any SMBG reading that was ≤70 mg/dL (3.9 mmol/L) without a diet- or activity-related cause, OR both a fasting glucose and a pre-evening meal SMBG ≤130 mg/dL (7.2 mmol/L) for 3 nonconsecutive days during the two weeks before Visit 2. |
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| E.5 End points |
| E.5.1 | Primary end point(s) | |
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
| |
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 11 |
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