| 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 | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
|
| 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 compare efficacy of two insulin treatment strategies in patients with type 2 diabetes who have inadequate glycemic control while treated with combination of premixed insulin analogue formulations (insulin lispro LM or biphasic insulin aspart 30/70) BID and metformin:
• the proposed strategy of upgrading treatment to insulin lispro MM/LM intensive mixture therapy in combination with metformin and
• the strategy of progressive dose titration of insulin analogue formulations BID combined with metformin, lifestyle and dietary intervention. This strategy reflects current common clinical practice.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
To evaluate the efficacy of treatment strategies measured with following parameters after 4 months of treatment (or at endpoint for patients who discontinue):
• Percentage of patients achieving HbA1c 7% and HbA1c 6.5% in both treatment groups
• 2-hour postprandial plasma glucose concentrations after the midday meal from self-monitored 7-point plasma glucose
• Mean 2-hour postprandial blood glucose excursions after midday meal
• Mean daily blood glucose levels
To compare the two treatments with respect to overall safety, including
• The incidence and rate of self-reported hypoglycemic episodes
• Change in weight from baseline to endpoint.
• To compare the total daily insulin dose in the treatment groups.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have type 2 diabetes (World Health Organization [WHO] classification).
2. Are at least 30 years of age and less than 75 years of age.
3. Have been receiving hypoglycemic treatment with premixed insulin analogue (either with insulin lispro LM or biphasic insulin aspart 30/70) administered twice daily in combination with at least 1500 mg of metformin per day for at least 60 days immediately prior to the study.
4. Have a hemoglobin A1c 1.2 to 1.8 times the upper limit of the normal reference range at the local laboratory at Visit 1
or
Have at least 6 of 9 of the postprandial blood glucose values recorded in the period between Visit 1 and Visit 2 exceeding 180 mg/dl [10.0 mmol/l].
5. As determined by the investigator, are capable and willing to
continue injections of insulin while continuing to use metformin as specified in inclusion Criterion [3],
learn how to use the insulin injection pen(s),
perform self blood glucose monitoring,
adjust doses of insulin according to the algorithm provided,
use the patient diary as required for this protocol,
be receptive to diabetes education
6. Have given written informed consent to participate in this study in accordance with local regulations. |
|
| E.4 | Principal exclusion criteria |
7. Are taking any other OAMs not mentioned in inclusion criterion [3].
8. Have a body mass index greater than 40 kg/m2.
9. Have had more than one episode of severe hypoglycemia, as defined in Section 6.4, within 6 months prior to entry into the study.
10. 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.
11. Are women who are breastfeeding.
12. have cardiac disease with functional status that is Class III or IV (American Hearth Association)
13. Have congestive heart failure.
14. Have a history of renal transplantation or are currently receiving renal dialysis.
15. Have obvious clinical signs or symptoms, or laboratory evidence, of liver disease (ALT or AST greater than 2 times the upper limit of the reference range as defined by the local laboratory).
16. Are undergoing therapy for a malignancy, other than basal cell or squamous cell skin cancer.
17. Have known hypersensitivity or allergy to any of the study drugs or excipients of the study drugs.
18. Have had a blood transfusion or severe blood loss in the opinion of the investigator within 3 months prior to Visit 1 or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia.
19. 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.
20. Have an irregular sleep/wake cycle (for example, patients who sleep during the day and work during the night).
21. Have any other condition (including known drug or alcohol abuse, psychiatric disorder) that precludes the patient from following and completing the protocol.
22. 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.
23. Are investigator site personnel directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
24. Are employed by Lilly. Immediate family of Lilly employees may participate in Lilly-sponsored clinical trials, but are not permitted to participate at a Lilly facility.
25. Have serum creatinine at a level that contraindicates metformin use according to the country-specific metformin product label.
26. Have known metabolic or lactic acidosis.
27. Have any condition associated with hypoperfusion, hypoxemia, dehydration, or sepsis.
28. Have had a radiologic contrast study within 48 hours prior to entry in the study or plan to have these procedures or surgery performed during the study.
Exclusion Criterion at Visit 2
29. During the period between Visits 1 and 2, had any episode of severe hypoglycemia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Summary of Study Design
Study F3Z-VI-S019 is a multicenter, randomized, open-label, 2-arm trial of parallel design. Approximately 270 patients with type 2 diabetes mellitus not achieving adequate glycemic control while treated with combination of premixed insulin analogue formulations (insulin lispro LM or biphasic insulin aspart 30/70) BID and metformin will be randomly assigned to follow one of two insulin treatment strategies used in combination with metformin administration: the proposed strategy of intensive mixture therapy with insulin lispro MM or the strategy of continuous progressive dose titration of premixed insulin analogue BID, diet and lifestyle modification. To achieve optimal metabolic control and explore full therapeutic potential of the strategies, patients in both arms will follow progressive insulin dose titration algorithms for 16 weeks.
Primary Efficacy Measure
The primary efficacy measure will be the central laboratory measurement of HbA1c at endpoint.
Secondary Efficacy Measures
• HbA1c change from baseline to endpoint,
• percentage of patients with HbA1c 7% and 6.5% at endpoint,
• the 2-hour postprandial plasma glucose concentrations after the midday meal from self-monitored 7-point plasma glucose profiles,
• mean 2-hour postprandial blood glucose excursions after midday meal and
• mean daily blood glucose levels. |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
|
| 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 | |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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