Trial document




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  DRKS00015855

Trial Description

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Title

A trial investigating the effect on blood glucose after the injection of fast-acting insulin aspart (Fiasp®) in comparison to insulin aspart (NovoRapid®) around exercise in participants with type 1 diabetes

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Trial Acronym

NN-ExFiasp®

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URL of the Trial

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Brief Summary in Lay Language

The study will compare changes in blood glucose concentrations of two insulins, Fiasp® and NovoRapid®, for the same pre- and post-exercise dose reduction (for both 2 x 50% and 2 x 75% reduced insulin dose) during exercise in 44 patients with type 1 diabetes (T1D). In this study, changes in several biological markers, before, during, and after exercise will be observed. The aim of this study is to help develop recommendations on how to adapt insulin therapy to achieve glucose control while exercising, in patients with type 1 diabetes. The study will recruit individuals (18-65 years) who exercise regularly with type 1 diabetes and will be based at the clinical research center at the Medical University of Graz. Participants who have been successfully screened will attend four main trial days. The trial days focus on the reduced bolus insulin doses of either Fiasp® or NovoRapid® at breakfast and lunch meals, separated by a 45 min session of moderate intensity aerobic exercise on a cycle ergometer. To compare effects of, and on, the insulins, blood tests will be taken at regular intervals (5 min, 10 min, 15 min and 20 min) throughout the visit.

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Brief Summary in Scientific Language

The study will compare changes in blood glucose 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, single-centre, double blind, four-period cross-over, twice dose trial. In this study, changes in several physiological markers, and blood markers before, during, and after exercise will be observed. The aim of this study is to help develop recommendations on how to adapt insulin therapy to achieve glucose control while exercising, in patients with type 1 diabetes. The study will recruit physically active individuals (18-65 years) with type 1 diabetes and will be based at the clinical research center at the Medical University of Graz. Participants who have been successfully screened will attend four main trial days. The trial days focus on the reduced bolus insulin doses of either Fiasp® or NovoRapid® at breakfast and lunch meals, separated by a 45 min session of moderate intensity aerobic exercise on a cycle ergometer. To compare effects of, and on, the insulins, blood tests will be taken at regular intervals (5 min, 10 min 15min , and 20 min) throughout the visit.

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Organizational Data

  •   DRKS00015855
  •   2019/06/12
  •   [---]*
  •   yes
  •   Approved
  •   31-314 ex 18/19, Ehtikkomission der Medizinischen Universität Graz
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Secondary IDs

  •   U1111-1234-6255 
  •   2019-001281-14 
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Health Condition or Problem studied

  •   E10 -  Type 1 diabetes mellitus
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Interventions/Observational Groups

  •   All participants will receive 50% reduced Fast-acting insulin aspart (Fiasp) bolus dose pre-exercise and post-exercise, using a 3mL FlexTouch pen-injector during this trial day visit. The trial drug will be administered subcutaneously in the abdomen and the dose level will be in accordance to patients' pre-meal carbohydrate factor.
  •   All participants will receive 75% reduced Fast-acting insulin aspart (Fiasp) bolus dose pre-exercise and post-exercise, using a 3mL FlexTouch pen-injector during this trial day visit. The trial drug will be administered subcutaneously in the abdomen and the dose level will be in accordance to patients' pre-meal carbohydrate factor.

  •   All participants will receive 50% reduced insulin Aspart (NovoRapid) bolus dose pre-exercise and post-exercise, using a 3mL FlexTouch pen-injector during this trial day visit. The trial drug will be administered subcutaneously in the abdomen and the dose level will be in accordance to patients' pre-meal carbohydrate factor.

  •   All participants will receive 75% reduced insulin Aspart (NovoRapid) bolus dose pre-exercise and post-exercise, using a 3mL FlexTouch pen-injector during this trial day visit. The trial drug will be administered subcutaneously in the abdomen and the dose level will be in accordance to patients' pre-meal carbohydrate factor.

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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Active control (effective treament of control group)
  •   Treatment
  •   Crossover
  •   IV
  •   No
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Primary Outcome

To compare changes in blood glucose concentrations of insulin Fiasp® and insulin 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, single-centre, double blind, four-period cross-over, twice dose trial.

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Secondary Outcome

• 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


• INSAUC+60 to +105 exercise: Pharmacokinetic 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 corrected (to time 0min) insulin AUC between +60min and +105min after first dosing (during exercise)
• INSAUC pre-exercise/first dosing: Pharmacokinetic 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 corrected (to time 0min) insulin incremental AUC from 0min to +30min and from +30min to +60min after first dosing
• INSAUC +105 to +240post-exercise/first dosing: Pharmacokinetic 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 corrected (to time 0min) insulin incremental AUC from +105 min to +150 min, from +150min to +195min and from +195min to +240min
• INSAUC a0 to ++240post-exercise/second dosing: Pharmacokinetic 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 corrected (to time a0min) insulin incremental AUC from a0min (second dosing) to ++60min, from ++60min to ++120min, from ++120min to ++180min and from ++180min to ++240min after second dosing
• ΔINSmax first dosing: Pharmacokinetic 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 insulin excursion after first dosing from 0min to +240min
• ΔINSmax second dosing: Pharmacokinetic 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 insulin excursion after second dosing from a0min to ++240min
• INSmax first dosing: Pharmacokinetic 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 insulin concentration after first dosing from 0min to +240min
• INSmax second dosing: Pharmacokinetic 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 insulin concentration after second dosing from a0min to ++240min.
• TΔINSmax first dosing: Pharmacokinetic 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 insulin excursion after first dosing from 0min to +240min
• TΔINSmax second dosing: Pharmacokinetic 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 insulin excursion after second dosing from a0min to ++240min
• Tmax first dosing: Pharmacokinetic 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 insulin concentration after first dosing from 0min to +240min
• Tmax second dosing: Pharmacokinetic 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 insulin concentration after second dosing from a0min to ++240min


• Hormonesexercise/: Comparison of hormonal response (adrenaline, noradrenaline, cortisol, IGF-1 and glucagon) between Fiasp® and NovoRapid® for the same insulin dose reduction, and within the same type of insulin in comparison of 50% vs. 75% insulin dose reduction at +60min, +82 min and +105min after first dosing during exercise
• Inflammationexercise/: Comparison of inflammatory response (IL-6, IL-9 and TNF-alpha) between Fiasp® and NovoRapid® for the same insulin dose reduction, and within the same type of insulin in comparison of 50% vs. 75% insulin dose reduction at +60min, +82 min and +105min after first dosing during exercise


• CGM24h post-second insulin dosing: Comparison of interstitial glucose for Fiasp® and NovoRapid® for the same insulin dose reduction, and within the same type of insulin in comparison of 50% vs. 75% insulin dose reduction from ++240 to 24h post-++240.
• CGMaccuracy: Comparison of CGM glucose to BG from 0min to +60min, from +60min to +105min, from +105min to +240min, from a0min to ++60min, from ++60min to ++105min, from ++105min to ++240min


• LAexercise: Comparison of blood lactate response between Fiasp® and NovoRapid® for the same insulin dose reduction, and within the same type of insulin in comparison of 50% vs. 75% insulin dose reduction at +60min, +82 min and +105min after first dosing during exercise
• Spirometryexercise: Comparison of continuous spirometric response between Fiasp® and NovoRapid® for the same insulin dose reduction, and within the same type of insulin in comparison of 50% vs. 75% insulin dose reduction after first dosing during exercise
• ECGexercise: Comparison of continuous ECG response between Fiasp® and NovoRapid® for the same insulin dose reduction, and within the same type of insulin in comparison of 50% vs. 75% insulin dose reduction after duringand around exercise

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Countries of Recruitment

  •   Austria
  •   United Kingdom
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Locations of Recruitment

  • other 
  • other 
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Recruitment

  •   Planned
  •   2019/06/24
  •   44
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   65   Years
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Additional Inclusion Criteria

•Male or female aged 18-65 years (both inclusive).
•Type 1 diabetes mellitus ≥ 12 months.
•Treated with multiple daily insulin injections ≥12 months.
•Body mass index 18.0-29.4 kg/m2 (both inclusive).
•Mass-specific VO2peak>20 ml/kg body weight/min.
•HbA1c≤9.5 % (80 mmol/mol)

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Exclusion Criteria

•Known or suspected hypersensitivity to trial product(s) or related products
•Receipt of any investigational medicinal product within 1 month prior to screening in this trial
•Known 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), alanine aminotransferase > 2 x the upper limit of normal (ULN), bilirubin > 3 x ULN, alkaline phosphatase > 2 x ULN
•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, ACE-inhibitors) as long as the therapy is stable and is not adapted throughout the run of the trial. Furthermore, it does not exclude 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.
•Participant with a heart rate < 40 beats per minute (bpm) at screening (after resting for 5 min in supine position)
•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
•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; therefore, if a repeated measurement on a second screening visit shows values within the range, the participant can be included in the trial). This exclusion criterion also pertains to participants being on antihypertensives (as long as the blood pressure is within the range, participants on hypertensives can be included)
•Clinically significant abnormal ECG at screening, as judged by the Investigator
•Proliferative retinopathy or maculopathy and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator
•Any chronic disorder or severe disease which, in the opinion of the Investigator might jeopardize participant’s safety or compliance with the protocol
•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
•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)
•Surgery or trauma with significant blood loss (more than 500 mL) within the last 3 months prior to screening
•Current treatment with systemic (oral or i.v.) corticosteroids, monoamine oxidase (MAO) inhibitors, non-selective or selective beta-blockers, growth hormone, herbal products or non-routine vitamins. Furthermore, thyroid hormones are not allowed unless the use of these has been stable during the past 3 months
•Significant history of alcoholism or drug/chemical abuse as per Investigator’s judgement.
•Smoker (defined as a participant who is smoking more than 5 cigarettes or the equivalent per day)
•Not able or willing to refrain from smoking, or use of nicotine substitute products during the inpatient period
•Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic event during the past 12 months).
•Hypoglycaemic unawareness as judged by the Investigator or hospitalisation for diabetic ketoacidosis during the previous 6 months
•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
•Potentially non-compliant or uncooperative during the trial, as judged by the Investigator.

•Any condition that would interfere with trial participation or evaluation of results, as judged by the Investigator
•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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Addresses

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    • Klinische Abteilung für Endokrinologie und Diabetologie, Medizinische Universität Graz
    • Mr.  Prof. Dr.  Harald  Sourij 
    • Auenbruggerplatz 15
    • 8036  Graz
    • Austria
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    • Klinische Abteilung für Endokrinologie und Diabetologie, Medizinische Universät Graz
    • Mr.  BSc  Harald  Kojzar 
    • Billrothgasse 12
    • 8010  Graz
    • Austria
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    • Klinische Abteilung für Endokrinologie und Diabetologie, Medizinische Universität Graz
    • Mr.  PD. Dr. Mag.  Othmar  Moser 
    • Billrothgasse 12
    • 8010  Graz
    • Austria
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Sources of Monetary or Material Support

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    • Novo Nordisk A/S
    • Mr. 
    • Novo Alle
    • 2880  Bagsvaerd
    • Denmark
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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