| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 1 Diabetes |
| Typ 1 Diabetes Mellitus |
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| E.1.1.1 | Medical condition in easily understood language |
| Participants in this study have type 1 diabetes which is defined as the lack of own insulin production. |
| Probanden in dieser Studie haben Typ 1 Diabetes Mellitus welches sich durch das Ausbleiben einer körpereigenen Insulinproduktion auszeichnet. |
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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 | 21.1 |
| 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 |
| • To compare changes in BG concentrations of Fiasp® and NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) during exercise in 44 patients with type 1 diabetes (T1D) in a randomised, multi-centre, double blind, four-period cross-over, twice dose trial. |
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| E.2.2 | Secondary objectives of the trial |
To compare:
• the pharmacodynamic effect of Fiasp® and NovoRapid® for the same pre- and post-exercise dose reduction (for both 2x50% and 2x75% reduced short-acting insulin dose) during exercise
• the pharmacodynamic effect of Fiasp® and NovoRapid® for the same pre- and post-exercise dose reduction (for both 2x50% and 2x75% reduced short-acting insulin dose) on BG excursions before and after exercise, around pre-exercise and post-exercise dosing
• the pharmacokinetic effect of Fiasp® and NovoRapid® for the same pre- and post-exercise dose reduction (for both 2x50% and 2x75% reduced short-acting insulin dose) on insulin excursions before, during and after exercise, around a pre-exercise and post-exercise dosing
• the counter-regulatory hormone, the inflammatory response, metabolic response, cardio-respiratory responses and CGM accuracy around exercise & 24h after 2nd dosing
• the interstitial glucose response of Fiasp® and NovoRapid® from 4h after 1st- to 28 hours after 2nd dosing
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Adults with type 1 diabetes mellitus (as diagnosed clinically) ≥ 12 months
• Treated with multiple daily insulin injections ≥ 12 months
• Body mass index 18.0-29.4 kg/m2 (both inclusive)
• Mass-specific peak oxygen consumption (VO2peak) >20 ml/kg/min
• HbA1c ≤ 9.5 % (80 mmol/mol)
• 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. Known haemoglobin < 8.0 mmol/l (<12.8 g/dl) (male) or < 6.4 mmol/l (10.3 g/dl) (female)
3. Systemic (oral or i.v.) corticosteroids, monoamine oxidase (MAO) inhibitors, non-selective beta-blockers, growth hormone and non-routine vitamins and herbal products. Furthermore, thyroid hormones are not allowed unless the use of these has been stable during the past 3 months.
4. Suffer from or history of a life-threatening disease (i.e. cancer judged not to be in full remission except basal cell skin cancer or squamous cell skin cancer), or clinically severe diseases that directly influence the study results, as judged by the Investigator. This does not prohibit the participation of patients taking medications that influences the metabolism (e.g. statin) or cardio-respiratory system (e.g. asthma spray) as long as the therapy is stable and is not adapted throughout the run of the trial. Furthermore, it does not excluded patients who have celiac disease (or similar diseases or allergies), as long as the disease is stable, and patients are able to stay on their specific (e.g.) gluten-free diet.
5. Participant with a heart rate < 40 beats per minute (bpm) at screening (after resting for 5 min in supine position)
6. Cardiac problems defined as decompensated heart failure (New York Heart Association (NYHA) class III and IV) 10 at any time and/or angina pectoris within the last 12 months and/or acute myocardial infarction at any time
7. Supine blood pressure at screening (after resting for 5 min in supine position) outside the range of 90-140 mmHg for systolic or 50-90 mmHg for diastolic (excluding white-coat hypertension; If white coat hypertension is observed then participants will be measured over 15 - 30 min every 5 min in a separate room and mean blood pressure will be used for eligibility assessment.). This exclusion criterion also pertains to participants being on anti-hypertensives
8. Clinically significant abnormal ECG at screening, as judged by the Investigator
9. Severe retinopathy or maculopathy and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator
10. Any chronic disorder or severe disease which, in the opinion of the Investigator might jeopardise participant’s safety or compliance with the protocol
11. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction (except celiac disease – patient must exclude foods that contain gluten from the diet)
12. Surgery or trauma with significant blood loss (more than 500 mL) within the last 3 months prior to screening
13. Participant known to be positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C antibodies (or diagnosed with active hepatitis), for HIV-1 antibodies, HIV-2 antibodies or HIV-1 antigen
14. Significant history of alcoholism or drug/chemical abuse as per Investigator’s judgement.
15. Smoker (defined as a participant who is smoking more than 5 cigarettes or the equivalent per day)
16. Not able or willing to refrain from smoking, or use of nicotine substitute products during the inpatient period
17. Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic event during the past 12 months)
18. Hypoglycaemic unawareness as judged by the Investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months
19. Participant with mental incapacity or language barriers precluding adequate understanding or cooperation or who, in the opinion of their general practitioner or the Investigator, should not participate in the trial
20. Potentially non-compliant or uncooperative during the trial, as judged by the Investigator
21. Any condition that would interfere with trial participation or evaluation of results, as judged by the Investigator
22. Female of childbearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods (adequate contraceptive measures include sterilisation, hormonal intrauterine devices, oral contraceptives, sexual abstinence or vasectomised partner).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • BG +60 to +105 exercise: Changes in BG concentrations of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) during exercise, as measured by changes over time in the corrected (to time 0min) BG concentrations between 60 and 105 min after first dosing (during exercise) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The timepoint for the primary endpoint will be from minute 60 to minute 105 after the first dosing (injection) during exercise. |
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| E.5.2 | Secondary end point(s) |
• BGAUC +60 to +105 exercise: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on BG excursions during exercise, as measured by the corrected (to time 0min) area under the glucose concentration–time curve (AUC) between 60 and 105 min after first dosing (during exercise)
• BGAUC pre-exercise/first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on BG for corrected (to time 0min) incremental AUC from 0min to +30min and from +30min to +60min after first dosing
• BGAUC +105 to +240post-exercise/first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on BG for corrected (to time 0min) incremental AUC from +105 min to +150 min, from +150min to +195min and from +195min to +240min.
• BGAUC a0 to ++240post-exercise/second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on BG for corrected (to time a0min) incremental AUC from a0min (second dosing) to ++60min, from ++60min to ++120min, from ++120min to ++180min and from ++180min to ++240min after second dosing
• ΔBGmax first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on maximum BG excursion after first dosing from 0min to +240min
• ΔBGmax second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on maximum glucose excursion after second dosing from a0min to ++240min
• BGmax first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on peak BG concentration after first dosing from 0min to +240min
• BGmax second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on peak BG concentration after second dosing from a0min to ++240min
• TΔBGmax first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on time to maximum glucose excursion after first dosing from 0min to +240min
• TΔBGmax second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on time to maximum glucose excursion after second dosing from a0min to ++240min
• Tmax first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on time to peak BG concentration after first dosing from 0min to +240min
• Tmax second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on time to peak BG concentration after second dosing from a0min to ++240min
• BGmin first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on minimum BG concentration after first dosing from 0min to +240min
• BGmin second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on minimum BG concentration after second dosing from a0min to ++240min
• Tmin first dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on time to minimum BG concentration after first dosing from 0min to +240min
• Tmin second dosing: Pharmacodynamic effect of Fiasp® compared with NovoRapid® for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced short-acting insulin dose) on time to minimum BG concentration after second dosing from a0min to ++240min
Also secondary endpoints for Insulin, Hormones, Inflammatory parameter, CGM, Metabolic Parameters, Spirometric Parameters and ECG during exercise will be investigated |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for the evaluation of all secondary outcomes will range from -5 minutes before the first dosing, up to 28 hours afterthe first dosing. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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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 | 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) | 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 | 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 | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 | Yes |
| 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 | 10 |
| 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 | 10 |
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