| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diabetes Mellitus type II (not insulin independent) |
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| 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 | 10012601 |
| E.1.2 | Term | Diabetes mellitus |
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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 of the study is to demonstrate non-inferiority of dry powder inhaled insulin (Exubera®) compared to insulin Glargine (Lantus®) in terms of glycemic control (HbA1c) after 26 weeks of treatment.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives of the study are to demonstrate superiority of inhaled insulin over insulin Glargine on the following endpoints: change of fasting glucose and postprandial glucose excursions from baseline to end of the treatment period, the percentage of subjects who have an HbA1c of less than 6.5%, 7.0%, or 8.0% at
the end of the treatment period, rates of overall and nocturnal hypoglycemia, changes in body weight and BMI, glucose excursions over 24 hours in a subset of subjects, and patient reported outcomes at week 26 compared to baseline. Additional secondary objectives are changes in urinary free 8 iso-prostaglandin F2α in a subset of patients, high sensitive C-reactive protein, interleukin 6 (IL-6), thrombin-antithrombin complexes (tat-complexes), and soluble tissue factor from baseline to end of the treatment period. |
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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 |
1. Exploratory 24-hour Glucose In-patient Substudy, 29th August, 2006
Substudy Objectives:
This is an exploratory study designed to assess the impact of treatment with Exubera or insulin glargine on various indices of glycemic stability over 24 hours and collect limited pharmacokinetic data.
2. Exploratory Urinary 8-iso Prostanes Substudy, 29th August, 2006
Title:
A comparison of mealtime inhaled insulin vs. subcutaneous basal insulin on glucose fluctuations and activation of oxidative stress as assessed by urinary 8-iso PGF2α in type 2 diabetes patients
Substudy Objectives:
The primary objective of this substudy is to explore whether pre-meal inhaled insulin (Exubera) results in less oxidative stress, as measured by urinary excretion of 8-iso PGF2α per 24 hour in type 2 diabetes patients failing on oral medication, compared to SC insulin glargine and whether differences are mediated by reduced glucose fluctuations, as measured by Mean Amplitude of Glycemic Excursions (MAGE) derived from 8 points blood glucose profiles taken concomitantly with the urine collection and during 24 hour continuous glucose monitoring in the exploratory subgroup.
Secondary aims are to investigate the relation between baseline demographic data, glycemic excursions as per parameters described in the master protocol, and oxidative stress.
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| E.3 | Principal inclusion criteria |
Male and female subjects meeting all of the following criteria will be considered for enrollment into the study.
1. Age ≥ 30 years with a diagnosis of type 2 diabetes mellitus made ≥ 6 months prior to study entry, as defined by the American Diabetes Association (Diabetes Care 25: S5-S20, 2002).
2. Screening HbA1c ≥ 7.0%
3. Currently treated on a stable dose of at least 2 oral hypoglycemic agents which must include combinations of sulfonylureas and metformin for at least 3 months prior to study entry. If a subject on a non-sulfonylurea secretagogue can be switched to glimepiride 2 mg at visit 2, they may be screened. Treatment with thiazolidinediones is permitted in addition to the sulfonylurea and metformin where concurrent treatment with insulin is permitted. |
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| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the trial:
1. Patients with Type 1 diabetes mellitus as defined by ADA.
2. Patients with type 2 diabetes mellitus currently (last three months) treated with an insulin regimen (only or associated to oral hypoglycemic agents (OHAs).
3. Patients with type 2 diabetes mellitus who are treated with thiazolidinediones where per local regulation concurrent use of insulin with thiazolidinediones is prohibited.
4. Patients taking any of the following hypoglycemic agents or agents within the following classes of drugs: repaglinide, nateglinide, exenatide, and dipeptidyl peptidase-4 inhibitors such as vildagliptin; rosiglitazone and pioglitazone where concurrent use of these agents with insulin is not permitted.
5. Active liver disease; significantly-impaired hepatic function, as shown by, but not limited to, ALAT (SGPT) or ASAT (SGOT) above 2x the upper limit of normal as measured at visit 1.
However, patients with elevated ALT >1.5 UNL as a result of hepatic steatosis are permitted to enter the study.
6. Significant kidney disease:
a. History of renal transplantation or current renal dialysis or
b. Serum creatinine > 1.5 mg/dl (≥ 133 µmol/L) in males and > 1.4 mg/dl (≥ 124 µmol/L) in females and/or BUN > 50 mg/dl or
c. Urinary albumin/creatinine ratio >2.5 mg/mmol in men and >3.5 mg/mmol in women or
d. Clinical nephrotic syndrome
7. Any other clinically significant abnormalities on screening laboratory evaluation (unless discussed with the monitor and approved by the study management).
8. Patients who do not have documentation of an ophthalmologic exam performed in the 12 months prior to visit 1 in accordance with local guidelines.
9. Active proliferative diabetic retinopathy, as defined by the application of focal or pan retinal photocoagulation or vitrectomy, in the 12 months prior to visit 1, or any other unstable (rapidly progressing) retinopathy that may require surgical treatment (including laser photocoagulation) during the study.
10. Donation of blood or transfusion during the 2 months prior to visit 1.
11. Pregnant or lactating women, or females of child-potential who are unwilling or unable to use adequate contraception to prevent pregnancy during the study.
12. Treatment with any investigational drug including inhaled insulin in the 3 months prior to visit 1 (screening).
13. Significant pulmonary diseases including:
o FEV1 <70% of predicted.
o History of moderate or severe asthma including those with daily symptoms and/or
require daily use of inhaled short acting beta2-agonist.
o History of moderate or severe COPD including those requiring regular use of one
or more bronchodilators (beta2-agonists, anticholinergics, methylxanthines).
However, short acting bronchodilators used as needed are allowed.Poorly controlled asthma, clinically significant obstructive pulmonary disease or other significant respiratory disease.
14. Smoking within the last 6 months prior to the study. Smoking is not permitted at any time during this study.
15. Mental condition rendering the patient unable to understand the nature, scope, and possible consequences of the study.
16. Any clinically significant major organ system disease such as relevant cardiovascular, gastrointestinal, hepatic, neurological, endocrine, haematological or other major systemic diseases making implementation of the protocol or interpretation of the study results difficult. However, wellcontrolled, stable disorders and complications directly related to diabetes (such as peripheral neuropathy, mild nephropathy or retinopathy) would not exclude a patient.
17. Treatment or likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol.
18. History of drug or alcohol abuse within the last 2 years or current addiction to substances of abuse.
19. Night shift workers.
20. Subject unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study.
21. Subject is the investigator or any sub investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
22. Subject is not willing and able to perform specified home blood glucose (HBGM) monitoring and to otherwise comply with study protocol requirements.
23. Subject who has not signed and dated informed consent prior to any study procedures.
24. Patients with contraindications according to the local prescribing information of sulfonylureas, Metformin, thiazolidinediones (where concurrent treatment with insulin is permitted), Exubera and Lantus
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change from baseline to HbA1c measured at week 26 (approx. 6 months) after treatment. |
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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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient reported outcomes |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 6 |
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