| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 |
| The primary objective of this study is to test the hypothesis that, for patients with type 2 diabetes who have inadequate glycemic control and are taking maximally tolerated doses of oral antihyperglycemic medications (OAMs) without insulin, initiating insulin use with one injection of insulin lispro mid mixture (MM), and progressing to up to three daily injections of premixed insulin lispro (thrice-daily insulin lispro MM with option of replacing the evening meal insulin lispro MM dose with insulin lispro low mixture (LM) added to existing oral therapy is noninferior to initiating insulin use with once daily insulin glargine and progressing to up to one to three additional injections of insulin lispro (glargine with or without lispro) added to existing oral therapy as measured by hemoglobin A1c (HbA1c) at endpoint. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to compare the insulin lispro MM arm and the insulin glargine arm with respect to:
• HbA1c at 12 weeks and 24 weeks
• in separate analyses, the percentage of patients who achieved HbA1c <=6.5%, <7%, and <=7% at 12 weeks, 24 weeks, 36 weeks, and at endpoint
• the 7-point self-monitored blood glucose (SMBG) profiles at baseline, 12 weeks, 24 weeks, 36 weeks, and at endpoint including glycemic variability and M-value
• insulin dose: total, basal, and prandial
• number of injections per day
• safety, as measured by the incidence and rate of self-reported hypoglycemic episodes, including nocturnal (and non-nocturnal) hypoglycemia; the incidence of severe hypoglycemia; weight change; and treatment-emergent adverse events. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Have type 2 diabetes (World Health Organization [WHO] classification, see Protocol Attachment IOOX.2).
2 Are at least 30 years old and less than 80 years old.
3 Have been receiving oral antihyperglycemic medications (OAMs) without insulin for at least 90 days immediately prior to the study, including at least two of the following OAMs at maximally tolerated doses, AND meet the additional dosing criteria shown:
Metformin: minimum dose of 1500 mg/day
Sulfonylurea: minimum dose of 1/2 the maximum daily dose, according to the local package insert.
Thiazolidinedione (TZD): minimum dose of 30 mg/day pioglitazone or 4 mg/day rosiglitazone
The OAMs also must be used in accordance with the product label and be approved for use with insulin in the patient’s country (Exclusion Criterion [7]). (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) >=7.5% and <= 12.0% as measured by a central laboratory at Visit 1.
5 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);
• use the patient diary as required for this protocol;
• be receptive to diabetes education, including continuing their prestudy diet and activity levels, or following simple dietary advice as appropriate;
• 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 Are taking a TZD dose greater than what is indicated in combination with insulin according to the TZD label in their respective country. (For example, in the US, rosiglitazone dose greater than 4 mg daily or pioglitazone dose greater than 45 mg daily is not currently indicated.) 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 least 2 weeks before the randomization visit (Visit 2).
8 Are taking any other glucose-lowering agents (such as meglitinide, alpha-glucosidase inhibitors, etc.) 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 40 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 cardiac disease with functional status that is Class III or IV (see Protocol Attachment IOOX.3); 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.
15 Have a history of renal transplantation or are currently receiving renal dialysis.
16 Have obvious clinical signs or symptoms, or laboratory evidence, of liver disease (alanine transaminase [ALT] or aspartate transaminase [AST] measurements greater than 2 times the upper limit of the reference range, as defined by the local laboratory).
17 Are undergoing therapy for a malignancy, other than basal-cell or squamous-cell skin cancer.
18 Have known hypersensitivity or allergy to any of the study insulins or excipients of the study insulins.
19 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.
20 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.)
21 Have an irregular sleep/wake cycle (for example, patients who sleep during the day and work during the night).
22 Have any other condition (including known drug or alcohol abuse or psychiatric disorder) that precludes the patient from following and completing the protocol.
23 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.
24 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.
25 Are Lilly employees.
For patients using metformin:
26 Have a serum creatinine concentration that contraindicates use of metformin according to the country-specific metformin product label.
27 Have known metabolic or lactic acidosis.
28 Have any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis.
29 Have had a radiologic contrast study within 48 hours prior to entry in the study or plan to have such a procedure or surgery performed during the study.
30 Exclusion Criteria at Visit 2: 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 <=140 mg/dL (7.8 mmol/L) for 3 consecutive days during the week before Visit 2. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Study F3Z-MC-IOOX is a randomized, multicenter, multinational, open-label, two-arm, active-control, parallel study utilizing dose titration and progressive intensification of insulin regimen with additional insulin injections. In this noninferiority study, insulin lispro mid mixture MM administered up to thrice daily will be compared with once-daily insulin glargine supplemented with up to three insulin lispro injections per day for 36 weeks in combination with existing oral antihyperglycemic medications (OAMs). Initial randomization to the two treatment arms will consist of approximately 500 patients currently on at least two OAMs but with inadequate diabetes control. Patients in both treatment groups will continue to take their prestudy OAMs along with the insulin treatment.
The primary efficacy measure is endpoint hemoglobin A1c (HbA1c) after 36 weeks of treatment.
The secondary measures of the study are to compare the treatments with respect to the following parameters:
• HbA1c at 12 weeks and 24 weeks
• Percentage of patients achieving HbA1c <=6.5%, <7%, and <=7% at 12 weeks, 24 weeks, 36 weeks, and at endpoint
• Blood glucose (BG) measures from 7-point self-monitored blood glucose (SMBG) profiles at 12 weeks, 24 weeks, 36 weeks, and at endpoint
• Insulin dose – total daily dose, daily basal dose, and daily prandial dose (U/day and U/kg/day)
• Number of injections per day
• Glycemic variability (for this study, defined as the standard deviation of a patient’s BG levels from 7-point BG profile from 1 day)
• M-value (mean BG based on 7-point SMBG)
An exploratory measure of the study is to compare the treatments with respect to the 7 point SMBGs at 18 and 30 weeks.
In addition, for each of the final insulin regimens (for example, insulin lispro mid mixture [MM] one time daily, insulin lispro MM two times daily [MM at morning meal + MM at evening meal or MM at midday meal + MM at evening meal], insulin lispro MM thrice daily, MM-MM-LM, glargine once-daily, glargine + lispro once daily, glargine + lispro twice daily, glargine + lispro thrice daily):
• List the percentage of patients on each regimen.
• List the respective HbA1c values at endpoint.
Patients’ responses to three questionnaires (Expectations About Insulin Therapy Questionnaire [EAITQ], Experiences With Insulin Therapy Questionnaire [EWITQ], and Insulin Device Satisfaction Questionnaire [IDSQ]) will be evaluated and compared between the two treatment groups.
Investigators are responsible for monitoring the safety of patients who have entered this study and for alerting Lilly or its designee to any event that seems unusual, even if this event may be considered an unanticipated benefit to the patient.
The investigator is responsible for appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, adverse events that are serious or that caused the patient to discontinue before completing the study. The patient should be followed until the event is resolved or explained. Frequency of follow-up evaluation is left to the discretion of the investigator.
Patients will be asked about any adverse events at each study visit, including the telephone visits. In addition to the standard safety measures, the following safety measures will be evaluated:
• Weight – change in patient weight in kilograms (kg) from baseline to endpoint.
• Hypoglycemia – rate per person per 30 days as well as incidence (total number of patients who experience hypoglycemia); nocturnal (and non-nocturnal) hypoglycemia; and incidence of severe hypoglycemia
• Blood pressure and heart rate. |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| 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 | 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
|
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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