| 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 | 7 | | E.1.2 | Level | LLT | | E.1.2 | Classification code | 10012601 | |
| 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 | | To demonstrate that mean reduction in HbA1c after 52 weeks (approx. 12 months) is greater in patients to whom inhaled insulin is made available compared to patients to whom it is not. | |
| E.2.2 | Secondary objectives of the trial | Secondary objectives of the study, although not literally stated, are reflected in the secondary endpoints. These endpoints are designed to show patients with inhaled option are more likely and quickly to use insulin, more likely to achieve and maintain glycemic control, and less likely to discontinue from the study. Other safety or efficacy aspects, such as hypoglycemia, weight gain, lipid profile, insulin antibodies and adverse events will also be studied. In addition, pharmacoeconomic impact will also be evaluated.
| |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | | 1.Age > 35 years and < 80 years with a diagnosis of type 2 diabetes made > 6 months prior to study entry, as defined by the American Diabetes Association (Diabetes Care 25:S5-S20, 2002).2.HbA1c > 8.0% at screening 3.Body Mass Index (BMI) > 23 kg/m2 and < 40 kg/m2 (See BMI Table Appendix E).4.Patients must have documentation of a fully dilated ophthalmologic exam performed within 1 year of screening in accordance with local guidelines. The documentation must be obtained prior to randomization. This information is of importance e.g., in case proliferative retinopathy is diagnosed while aggressive glucose lowering is considered in the study. 5.Currently treated and on a stable dose at least two oral hypoglycemic agents for at least 3 months prior study entry at the following minimum doses: ·Sulfonylurea dosage greater than or equal to one half the maximum recommended dosage i.e. glimepiride > 4 mg; glipizide, including GITS ³ 10 mg; or glyburide ³ 10 mg, or Glynase® ³ 3 mg; Gliclazide in any dosing ³ 180 mg daily, or Gliclazide MR in any dosing ³ 15 mg daily·Metformin dosage ³ 1500 mg daily including Glucophage XR® ·Fixed combination of glyburide and metformin e.g., Glucovance® in any dosing in which glyburide ³ 10 mg and metformin > 1000 mg daily·Rosiglitazone e.g., Avandia® in any dosing ³ 4 mg daily·Pioglitazone e.g., Actos® in any dosing ³ 30 mg daily·Repaglinide e.g., Prandin® in any dosing ³ 2 mg before meals·Nateglinide e.g., Starlix® in any dosing ³ 60 mg before meals·Acarbose e.g., Precose™ in any dosing ³ 300 daily·Miglitol e.g., Glyset® in any dosing ³ 150 mg daily6.Written informed consent obtained PRIOR to performing screening evaluations. | |
| E.4 | Principal exclusion criteria | | 1.Type 1 diabetes 2.Known allergy to insulin 3.Smoking: current or any in the past 6 months; smoking is not permitted at any time during the study4.Current treatment with insulin or discontinued from insulin within the past three months5.“Brittle” diabetes or a predisposition to severe hypoglycemia, i.e., 2 or more severe hypoglycemic episodes within the past 6 months, or any hospitalization or emergency room visit due to poor diabetic control (other than for hypoglycemia) within the past 6 months. Similarly, during the baseline run-in period, any patient with more than one severe hypoglycemic episode, or any hospitalization or emergency room visit due to poor diabetic control (other than for hypoglycemia), will be excluded from randomization. Severe hypoglycemia is defined in Section 10.11.2. of the protocol.6.Metabolic Conditions:a)Significant hypoglycemia risk e.g., history of >2 severe (DCCT) hypoglycemic episodes within past 6 months, known adrenal insufficiency, symptomatic autonomic neuropathy b)Current chronic inhaled or systemic corticosteroid treatment likely to be of metabolic effect (prednisone equivalent >2 mg/day); intercurrent treatment at a higher dose is allowed if treatment duration does not exceed 2 weeks7.Active Liver disease; ALT > 1.5 times the upper limit of normal reference range for the central lab at screening. Evidence within the preceding six months of hepatic dysfunction e.g., AST, ALT, two and a half (2.5) times the upper limit of normal or hepatic disease, e.g., hepatitis, jaundice, cirrhosis or history of developing abnormal liver function tests (LFTs) on thiazolidinediones.8.Pulmonary Conditions:a)Frankly abnormal PFTs at Week –1, defined as DLco >120% or <70%; TLC >130% or <70%; or FVC or FEV1 <70% of predicted.b)Clinically significant abnormalities on screening chest X-ray (or chest MRI). A screening chest x-ray or chest MRI is defined as a chest x-ray or chest MRI obtained at screening or 6 months prior to screening. Subjects with radiographically stable and clinically insignificant abnormalities need not be excluded (e.g., localized scarring or calcified granulomata). Documentation of stability requires comparison with previous radiographs obtained at least 6 months earlier. c)Significant pulmonary diseases including:·History of moderate or severe asthma including those with daily symptoms and/or require daily use of inhaled short acting beta2-agonist.·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 (prn) are allowed. ·Poorly-controlled asthma, clinically significant obstructive pulmonary disease or other significant respiratory disease. 9.Cardiovascular conditions:a)Significant cardiovascular dysfunction and/or history including hospitalization within the preceding six months, e.g., congestive heart failure or serious arrhythmia, myocardial infarction, cardiac surgery, recurrent syncope, transient ischemic attacks or cerebrovascular accident.b)Poorly-controlled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg) on two readings (sitting).c)Abnormal screening ECG: i)predominant rhythm other than normal sinusii)A-V block greater than first degree iii)resting heart rate > 100 or < 50 bpm The principal investigator, or other designated physician at each site, will be responsible for deciding the clinical significance of any abnormal ECG findings.10.Kidney disease:a) History of renal transplantation or current renal dialysis b) Clinical nephrotic syndrome, or significant renal dysfunction or disease based on estimated creatinine clearance < 65 mL/min (25), and/or a serum creatinine greater or equal to 1.5 mg/dl (133 mmol/L) in males and greater or equal to 1.4 mg/dl (124 mmol/L) in females and /or BUN >50 mg/dl, whichever is worse. 11.Psychologicala)History of substance abuse or alcoholism within the past 5 yearsb)Psychiatric disorders that would interfere with the patient’s ability to complete the study 12.Neurologicala)Seizure disorderb)Significant gastroparesis or orthostatic hypotension (autonomic neuropathy)13.Any current malignancy except:a)those ³ 5 years ago without recurrenceb)excised basalioma or squamous cell cancer14.Clinically significant abnormalities on screening laboratory evaluation (unless discussed with and approved by a Pfizer clinician) | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary objective of this study is to demonstrate that mean the reduction in HbA1c after 52 weeks (approx. 12 months) of treatment is greater in patients to whom inhaled insulin is made available compared to patients to whom it is not. Thus, the primary efficacy variable is the difference in HbA1c between baseline (Week -1) and the end of the treatment period at week 52, in the intention-to-treat (ITT) population | |
| 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 | Yes |
| 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) | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | |
| 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 | |
| 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 | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
