| 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 26 weeks (approx. 6 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 endpoints which will be assessed at endpoint (12 months) and at week 26 (approx. 6 months) as part of an interim analysis:
· HbA1c at week 52, ITT population
· Proportion of patients achieving glycemic control (HbA1c ≤ 6.5%, ≤ 7.0%)
· The time it takes to get to “be treated with” insulin (inhaled or SC)
· Change from baseline in fasting plasma glucose level
· Incidence and severity of hypoglycemia
· Change from baseline in body weight and body mass index
· Change from baseline in fasting lipid profile
· Treatment categories: Inhaled insulin, SC insulin, changed oral agents, no change in treatment choice.
· Number of patients who discontinue due to insufficient clinical response
· Pulmonary function
· Insulin antibody titers
· Incidence of clinical adverse events
· Pharmaco-economic impact
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Male and female patients meeting all criteria listed below will be included in the study:
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 of at least two oral hypoglycemic agents for at least 3 months prior study entry with at least half maximum dose per country guidelines or half maximum tolerable dose.
6. 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 study
4. Current treatment with insulin or discontinued from insulin within the past three months
5. “Brittle” diabetes or a predisposition to severe hypoglycemia. Severe hypoglycemia is defined in Section 10.11.2. of the protocol.
6. Metabolic Conditions:
a) Significant hypoglycemia risk
b) Current chronic inhaled or systemic corticosteroid treatment likely to be of metabolic effect
7. Active Liver disease
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). Subjects with radiographically stable and clinically insignificant abnormalities need not be excluded. Documentation of stability requires comparison with previous radiographs obtained at least 6 months earlier.
c) Significant pulmonary diseases
9. Cardiovascular conditions:
a) Significant cardiovascular dysfunction and/or history including hospitalization within the preceding six months.
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 sinus
ii) 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 µmol/L) in males and greater or equal to 1.4 mg/dl (124 µmol/L) in females and /or BUN >50 mg/dl, whichever is worse.
11. Psychological
a) History of substance abuse or alcoholism within the past 5 years
b) Psychiatric disorders that would interfere with the patient’s ability to complete the study
12. Neurological
a) Seizure disorder
b) Significant gastroparesis or orthostatic hypotension (autonomic neuropathy)
13. Any current malignancy except:
a) those ≥ 5 years ago without recurrence
b) excised basalioma or squamous cell cancer
14. Clinically significant abnormalities on screening laboratory evaluation
15. Clinically significant major organ system disease
16. Patients with circumstances or abnormalities (e.g., blindness or a history of non-compliance) that would interfere with the interpretation of safety or efficacy data or the completion of the study
17. Unable and/or unlikely to comprehend and/or follow the study protocol (including blood glucose monitoring) and complete Patient Reported Outcomes questionnaire. Unable and/or unlikely to comprehend how to use the inhaler device or inability to use the inhaler device
18. Failure to adhere to protocol requirements during the run-in period
19. Pregnant or intent to become pregnant OR BREASTFEEDING during study or absence of adequate birth control measures
20. Inpatient surgery anticipated during the study period
21. Known interference with HbA1c determination: hemoglobinopathy or chronic anemia
22. Investigator or immediate family
23. Donation of blood or blood products for transfusion during the 30 days prior to initiation of treatment with study drug (if applicable), at any time during the study or 30 days after completion of the study
24. Participation in any other studies involving investigational or marketed products within the two (2) months prior to entry in the study
25. Participation in any prior Inhaled insulin or other inhaled insulin clinical trials, including participation in the “Real World Feasibility Study” (A2170003), excludes patients from entry into this study
| |
| 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 26 weeks (approx. 6 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 -2) 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 38 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 105 |
| 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 | 12 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
