E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
type II diabetes mellitus |
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MedDRA Classification |
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 |
Initiation Phase The primary objective of the 6-month initiation phase of this study of patients with type 2 diabetes with inadequate glycemic control is to test the hypothesis that addition of twicedaily insulin lispro LM to existing OAM therapy as compared to the addition of once daily insulin glargine will result in greater reduction in endpoint HbA1c adjusted for baseline HbA1c. Maintenance phase The primary objective of the two-year maintenance phase of this study is to test the hypothesis that the addition of twice-daily insulin lispro LM to existing OAMs results in a longer durability of glycemic control than the addition of once daily insulin glargine such that more subjects will remain at HbA1c goal (HbA1c at ≤7.0% or >7.0% but with an increase of less than 0.4% from the last HbA1c ≤7.0%). Durability is defined as the duration of time for maintaining the HbA1c at goal. Addendum To compare the endpoint HbA1c. |
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E.2.2 | Secondary objectives of the trial |
Initiation Phase (1) To compare the safety and efficacy of the two regimens (insulin lispro LM plus OAMs and insulin glargine plus OAMs) during the initiation phase (2) To compare the baseline and endpoint characteristics of the patient populations that failed to achieve HbA1c goal, with those that succeeded in achieving goal during the initiation phase. Maintenance phase (3) To compare the safety and efficacy of the two primary insulin regimens during the maintenance phase (4) To compare the baseline and endpoint characteristics of the patient populations that failed to maintain the HbA1c goal, with those that succeeded in maintaining goal during the maintenance phase. Addendum To compare second step intensification insulin regimens (in subjects who have failed to achieve HbA1c ≤7% during 6 months of either insulin glargine therapy or twice-daily insulin lispro LM therapy).
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
[1] Have type 2 diabetes (World Health Organization [WHO] classification, see Protocol Attachment IOOV.3). [2] Are at least 30 years of age and less than 80 years of age. [3] Have been receiving oral diabetes therapy for at least 90 days immediately prior to the study that includes at least 2 of the following OAMs AND meets the additional criteria shown: OAM Minimum Dose: Metformin 1500 mg/day, Sulfonylurea ½ the maximum daily dose, TZD 30 mg/day pioglitazone or 4 mg/day rosiglitazone. [4] Have an HbA1c 1.2 to 2.0 times the upper limit of the normal reference range at the local laboratory at Visit 1. [5] As determined by the investigator, are capable and willing to: • use the insulin injection device (or syringe and vial) according to the instructions provided; • inject insulin while continuing to use the pre-study regimen of OAMs specified in Inclusion Criterion [3]; • perform self monitoring of blood glucose; • use the subject diaries as required for this protocol; • be receptive to diabetes education; • comply with the required study visits and willing to receive regular telephone calls between visits. [6] Have given written informed consent to participate in this study in accordance with local regulations. |
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E.4 | Principal exclusion criteria |
[7] Prior scheduled long-term insulin therapy within the past 12 months. NOTE: Subjects who have previously received short-term insulin therapy (during pregnancy, an acute hospitalization or for occasional use) will be allowed to participate. Occasional use (e.g., used to treat acute hyperglycemia) shall be defined as less than daily administration of not more than 1 dose per day of insulin. [8] Are taking any other OAMs not mentioned in Inclusion Criterion [3]. [9] 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. [10] Have a body mass index greater than 45 kg/m2. [11] Have had more than one episode of severe hypoglycemia, as defined in the Abbreviations and Definitions section, within 24 weeks prior to entry into the study. [12] 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. [13] Are women who are breastfeeding. [14] Have one of the following concomitant diseases: presence of clinically significant hematologic, oncologic, renal, cardiac, hepatic, or gastrointestinal disease. [15] Have cardiac disease with functional status that is Class III or IV (see Protocol Attachment IOOV.4). [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] greater than 2 times the upper limit of the reference range, as defined by the local laboratory). [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] Are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within the 4 weeks immediately preceding Visit 1. [22] Have an irregular sleep/wake cycle (for example, subjects 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 subject 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 the 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. For subjects using metformin: [27] Have a serum creatinine concentration that contraindicates metformin use 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The study is a randomized, multicenter, multinational, open-label, 2-arm, parallel study comparing twice-daily insulin lispro LM to once daily insulin glargine for 30 months in combination with existing OAMs. Initial randomization between either insulin lispro LM (twice-daily) or insulin glargine (once daily) will consist of 2000 subjects currently on at least 2 OAMs but with inadequate diabetes control who are about to initiate insulin therapy. Subjects in both treatment groups will continue to take their prestudy OAMs along with the insulin treatment. During the 6-month initiation phase, insulin doses will be adjusted to achieve a goal of HbA1c ≤6.5% and SMBG targets as described in the insulin dose adjustment algorithms. Those subjects with an HbA1c ≤7.0% at 6 months will continue in the main arms of the study for an additional 24-month maintenance phase. During the maintenance phase, subjects will only discontinue if serum HbA1c rises above 7.5%. However, for the assessment of durability, failure of the regimens will be defined as HbA1c >7.0% with a rise of ≥0.4% HbA1c from the most recent HbA1c ≤7.0%. In the maintenance phase, subjects will continue to have their insulin doses adjusted to maintain the same glycemic goals (HbA1c ≤6.5%) and SMBG targets. Stratification of the randomization scheme is to be within country, and by TZD and sulfonylurea use. Those subjects that will not achive an HbA1c ≤7.0% at 6 months will be randomized to a 6 -month addendum study until the sample size required has been reached (n=386 from each arm of initiation phase). Subjects from the insulin glargine arm will be randomized to a second step intensification regimen consisting of either twice-daily lispro LM or basal-bolus therapy (using insulin glargine and insulin lispro) and subjects from the insulin lispro LM arm will be randomized to a second step intensification regimen consisting of either thrice-daily lispro MM or basal-bolus therapy (using insulin glargine and insulin lispro). |
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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 | Information not present in EudraCT |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |