E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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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 |
•Assessment of the linearity of the dose response curves (based on AUCINS,0-∞, CMAX,INS, AUCGIR,0-12h and GIRMAX) of inhaled insulin
•Comparison of the inter- and intra-subject variability (based on AUCINS,0-∞, CMAX,INS, AUCGIR,0-12h and GIRMAX) of inhaled insulin with subcutaneous insulin (Humalog®, insulin lispro) administration
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E.2.2 | Secondary objectives of the trial |
•Assessment of the pharmacokinetic and pharmacodynamic responses at three dose levels of inhaled insulin
•Comparison of the pharmacokinetic and pharmacodynamic responses after 1 actuation of 9 IU high-concentration (900 IU/mL) inhalation formulation versus 3 actuations of the 3 IU low-concentration (300 IU/mL) inhalation formulation
•Assessment of the relative efficiency of inhaled insulin
•Safety and tolerability of the inhaled insulin
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Type 2 diabetes mellitus for more than 12 months
•Treated with one or multiple daily insulin injections for more than 3 months
•Concomitant treatment with metformin in stable doses will be permitted (and continued throughout the trial).
•Body mass index (BMI) between 25.0-40.0 kg/m² (both inclusive)
•Fasting C-peptide ≤ 1.0 nmol/l
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E.4 | Principal exclusion criteria |
•Clinically significant abnormal haematology, biochemistry, lipids, urinalysis or coagulation screening tests, as judged by the Investigator considering the underlying disease
•Cardiac disease
•Hepatic insufficiency
•Impaired renal function
•Current treatment with systemic corticosteroids, MAO inhibitors, prostaglandin blockers, systemic non-selective beta-blockers, growth hormone, and other drugs, which may interfere with glucose metabolism. Furthermore, thyroid hormones are not allowed unless the use of these has been stable during the past 3 months.
•Uncontrolled treated/untreated hypertension
•Any condition possibly affecting drug absorption from the lung, in particular subjects with decreased lung function or subjects taking bronchodilators.
•Any active or chronic pulmonary disease as documented by history, physical examination or pulmonary function tests at screening.
•Current smoker |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary pharmacokinetic endpoints
1. AUCINS,0-∞
2. CMAX,INS
3. Dose-exposure relationship
4. Inter- and intra-subject variability
Primary pharmacodynamic endpoints
1. AUCGIR,0-12h
2. GIRMAX
3. Dose-response relationship
4. Inter- and intra-subject variability |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary pharmacokinetic endpoints
1. from 0 hours to infinity
2. maximum observed insulin human / insulin lispro concentration
3. based on AUCINS 0 ∞ and CMAX,INS
4. based on AUCINS,0-∞, CMAX,INS
Primary pharmacodynamic endpoints
1. from 0 to 12 hours
2. maximum observed GIR
3. based on AUCGIR 0 12h and GIRMAX
4. based on AUCGIR,0-12h and GIRMAX |
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E.5.2 | Secondary end point(s) |
Secondary pharmacokinetic endpoints
1. AUCINS,0-1h
2. AUCINS,0-2h
3. AUCINS,0-4h
4. AUCINS,0-12h
5. TMAX,INS
6. FREL
7. Onset of appearance
8. t1/2-INS
9. MRTINS
Secondary pharmacodynamic endpoints
1. AUCGIR,0-1h
2. AUCGIR,0-2h
3. AUCGIR,0-4h
4. TGIR,MAX
5. t50%-GIR
6. GREL
7. Duration of action |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary pharmacokinetic endpoints
1. from 0 to 1 hour
2. from 0 to 2 hours
3. from 0 to 4 hours
4. 0 to 12 hours
5. time to maximum observed insulin human / insulin lispro concentration
6. from 0 to infinity
7. time from trial product administration until the first time serum insulin concentration > LLOQ
8. terminal half-life of insulin
9. mean residence time of insulin
Secondary pharmacodynamic endpoints
1. from 0 to 1 hour
2. from 0 to 2 hours
3. from 0 to 4 hours
4. time to maximum GIR
5. time to half-maximum glucose infusion rate before and after GIRmax (early and late)
6. relative biopotency of (inhaled) insulin human compared to (sc injected) insulin
7. ongoing |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 | No |
E.8.1.6 | Cross over | Yes |
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.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |