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 | 15.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045228 |
E.1.2 | Term | Type I 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 |
•Comparison of the pharmacokinetic response after inhaled insulin administration with 3 different inhalation regimens (output mesh specifications)
•Assessment of the relative bioavailability of inhaled insulin
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E.2.2 | Secondary objectives of the trial |
•Comparison of the relative pharmacokinetic (based on AUCINS,0-8h and CMAX,INS) properties of inhaled human insulin with subcutaneous insulin (Humalog®, insulin lispro) administration
•Comparison of the postprandial glucose response after inhaled insulin administration with 3 different inhalation regimens
•Comparison of the postprandial glucose response after inhaled insulin administration and subcutaneous insulin administration
•To derive an estimate of the intravariability of PK and PD parameters with the medium output mesh insulin inhalation
•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 |
1.Signed and dated informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.
2.Male or female subjects aged 18–64 years (both inclusive).
3.Type 1 diabetes mellitus (as diagnosed clinically) ≥ 12 months.
4.Treated with multiple daily insulin injections or continuous subcutaneous insulin infusion (CSII) ≥ 12 months.
5.Current total daily insulin treatment < 1.2 (I)U/kg/day.
6.Body mass index 18.0–28.0 kg/m2 (both inclusive).
7.Glycated haemoglobin (HbA1c) ≤ 9.0 % by local laboratory analysis.
8.Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) ≥ 75 % of predicted normal values for race, age, gender and height.
9.Fasting C-peptide < 0.3 nmol/L
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E.4 | Principal exclusion criteria |
1.Known or suspected hypersensitivity to trial product(s) or related products.
2.Previous participation in this trial. Participation is defined as randomised.
3.Subjects with any condition possibly affecting drug absorption from the lung.
4.Subject has any active or chronic pulmonary disease as documented by history, physical examination or pulmonary function tests at screening.
5.Receipt of any investigational medicinal product within 30 days before randomisation in this trial.
6.Haemoglobin < 8.0 mmol/L (male) or < 6.4 mmol/L (female), total leukocyte count < 3.0 x 109/L, thrombocytes <100 x 109/L, serum creatinine levels ≥ 126 µmol/L (male) or ≥ 111 µmol/L (female), bilirubin > 3 x the upper limit of normal (ULN), and alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (γ-GT) > 2 x ULN.
7. Smoker
8. Female of childbearing potential who is pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. AUCINS,0-8h, area under the insulin human / insulin lispro concentration-time curve
2. FREL, relative bioavailability of (inhaled) insulin human compared to (sc injected) insulin lispro |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. from 0 to 8 hours
2. from 0 to 8 hours |
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E.5.2 | Secondary end point(s) |
Secondary pharmacokinetic endpoints
1.AUCINS,0-1h, area under the insulin human / insulin lispro concentration-time curve
2. AUCINS,0-2h, area under the insulin human / insulin lispro concentration-time curve
3. AUCINS,2-8h, area under the insulin human / insulin lispro concentration-time curve
4. CMAX,INS
5. TMAX,INS
6. Onset of appearanceINS
Secondary pharmacodynamic endpoints
1. ∆AUCBG,0-1h, area under the blood glucose concentration-time curve
2. ∆AUCBG,0-2h, area under the blood glucose concentration-time curve
3. ∆AUCBG,0-8h, area under the blood glucose concentration-time curve
4. ∆AUCBG,2-8h, area under the blood glucose concentration-time curve
5. ∆BGMAX, maximum blood glucose excursion
6. BGMAX, maximum blood glucose concentration
7. TBG,MAX, time to maximum blood glucose concentration |
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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 2 to 8 hours
4. maximum observed insulin human / insulin lispro concentration
5. time to maximum observed insulin human / insulin lispro concentration
6.time from trial product administration until the first time insulin human / insulin lispro concentration ≥ LLOQ
Secondary pharmacodynamic endpoints
1. from 0 to 1 hour after standard meal consumption
2. from 0 to 2 hours after standard meal consumption
3. from 0 to 8 hours after standard meal consumption
4. from 2 to 8 hours after standard meal consumption
5. after standard meal consumption
6. after standard meal consumption
7. after standard meal consumption |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | 5 |
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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |