E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 1 diabetes |
Type 1 diabetes |
|
E.1.1.1 | Medical condition in easily understood language |
Diabetes, Sugar disease |
Suikerziekte |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
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 investigate the effect of treatment with the SGLT-2 inhibitor dapagliflozin on the
awareness of and counterregulatory hormone responses to
hypoglycemia in people with type 1 diabetes and impaired
hypoglycemic awareness |
Onderzoeken van effect van behandeling met de SGLT-2 remmer dapagliflozine op de symptomatologie van en hormonale respons op
hypoglykemieën bij patiënten met type 1 diabetes en verminderde
hypoglykemie awareness (IAH, impaired awareness of hypoglycemia) |
|
E.2.2 | Secondary objectives of the trial |
To investigate the effect of treatment with the SGLT-2 inhibitor dapagliflozin on the
glycemic recovery from hypoglycemia and the post-hypoglycemic
glucose excursion in people with type 1 diabetes and impaired awareness of hypoglycemia |
Onderzoeken van effect van behandeling met de SGLT-2 remmer dapagliflozine op het glucoseherstel en de mate van glucosestijging na
hypoglykemie bij patiënten met type 1 diabetes en verminderde
hypoglykemie awareness |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Type 1 diabetes, disease duration >1 year
• Age >18 years, <75 years
• BMI 19-30 kg/m^2
• Insulin treatment according to basal-bolus insulin regimen (injections
or insulin pump)
• Impaired awarenessof hypoglycemia as assessed by a score of 3 or
more on the modified Dutch translation of the Clarke questionnaire
• Glycated haemoglobin (HbA1c) ≥42 mmol/mol (6%) and ≤75
mmol/mol (9.0%)
• Ability to provide informed consent |
• Type 1 diabetes met een duur van tenminste 1 jaar
• Leeftijd ouder dan 18 jaar en jonger dan 75 jaar
• BMI tussen 19-30 kg/m^2
• Insulinebehandeling volgens het zg. basaal-bolus principe met
injecties of een subcutane pomp
• Impaired awareness of hypoglycemia gedefinieerd als tenminste 3
punten (van max. 5) op de in het Nederlands vertaalde IAH-vragenlijst
van Clarke
• HbA1c ≥42 mmol/mol (6%) en ≤75 mmol/mol (9.0%)
• Voldoende in staat om informed consent te geven |
|
E.4 | Principal exclusion criteria |
• Known intolerance to SGLT-2 inhibitors (including allergy)
• Treatment with glucose-modefying or immune-modefying agents, e.g.
prednisolon
• Treatment with pioglitazone
• History of cardiovascular disease (e.g. myocardial infarction, stroke, heart failure, symptomatic peripheral arterial disease) or hypotension
• Conditions that can lead to volume depletion (acute gastro-intestinal diseases)
• History of galactose-intolerance, lactase deficiency, glucose-galactose malabsorption
• History of diabetic ketoacidosis requiring medical intervention within 1 month before screening
• Admission to the hospital for hyper- or hypoglycemia <1 month before screening
• Frequent episodes of severe hypoglycemia <1 month before screening
• History of laser coagulation for proliferative
retinopathy (past 6 months)
• Proliferative retinopathy
• Symptomatic diabetic neuropathy
• Diabetic nephropathy as reflected by albumin-creatinin ratio >30
mmol/mg or MDRD <60 ml/min/1.73 m2
• History of pancreatitis (acute or chronic) or pancreatic cancer
• Use of premixed insulin or of long-acting insulin alone
• Total daily insulin dose requirements <20 units unless on pump
treatment
• Pregnancy or unwillingness to undertake measures for birth control |
• Bekende intolerantie of allergie voor SGLT-2 remmers
• Behandeling met pioglitazon
• Behandeling met medicijnen die invloed hebben op het glucosemetabolisme of immuunsysteem, zoals prednisolon
• Voorgeschiedenis van een hart- en vaatziekten (bijvoorbeeld myocardinfarct, beroerte, hartfalen, perifeer arterieel vaatlijden) of hypotensie
• Bekend met aandoeningen die kunnen leiden tot volume depletie (acute gastro-intestinale ziekte)
• Voorgeschiedenis van galactose-intolerantie, lactase deficiëntie, glucose-galactose malabsorptie
• Voorgeschiedenis van diabetische ketoacidose waarvoor medische interventie noodzakelijk was <1 maand voor screening
• Ziekenhuisopname voor hyper- of hypoglykemie <1 maand voor screening
• Frequente episodes van ernstige hypoglykemie <1 maand voor screening
• Voorgeschiedenis van laserbehandeling voor proliferatieve retinopathie in de afgelopen 6 maanden
• Proliferatieve retinopathie
• Symptomatische diabetische neuropathie
• Diabetische nefropathie, weerspiegeld door een albumine-kreatine ratio van >30 mmol/mg en/of een MDRD <60 ml/min/1.73 m2
• Voorgeschiedenins van pancreatitis (acuut of chronisch) of pancreaskanker
• Gebruik van voorgemixt insuline of behandeling met alleen langwerkend insuline
• Totale insulinebehoefte van minder dan 20 eenheden per dag, tenzij behandeld met een insulinepomp
• Zwangerschap of niet bereid tot het gebruiken van voorbehoedsmiddelen |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Maximal symptom score in response to hypoglycemia during the hyperinsulinemic
hypoglycemic glucose clamp experiment |
Maximale symptoomscore tijdens hypoglykemie gedurende het hyperinsulinemische
hypoglykemische glucose clamp experiment |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
During hypoglycemic glucose clamp after 8 weeks of treatment |
Gedurende de hypoglykemische glucose clamp na 8 weken behandeling |
|
E.5.2 | Secondary end point(s) |
- Responses of counterregulatory hormones ((nor)adrenaline, glucagon,
cortisol, growth hormone) to the hyperinsulinemic hypoglycemic
glucose clamp
- Time until glycemic recovery from hypoglycemia after the
hyperinsulinemic glucose clamp
- Maximal glucose excursion post-hypoglycemia after the
hyperinsulinemic glucose clamp
- Time until glucose peak post-hypoglycemia after the hyperinsulinemic
glucose clamp
- The inflammatory/atherogenic phenotype of circulating monocytes
- Area under the glucose concentration curve post-hypoglycaemia after
the hyperinsulinemic glucose clamp
- Hunger score post-hypoglycemia after the hyperinsulinemic glucose
clamp
- Number of severe hypoglycemic events during 8 weeks of treatment
with dapagliflozin or placebo
- Number of nocturnal hypoglycemic events during 8 weeks of
treatment with dapagliflozin or placebo
- Number of any hypoglycemic events during 8 weeks of treatment with
dapagliflozin or placebo
- Number of hypoglycemic events and time spent under hypoglycemic
conditions as measured by continuous glucose sensor monitoring
- Glucose variability as measured by continuous glucose sensor
monitoring
- Vital signs during the hyperinsulinemic hypoglycemic glucose clamp
- Percentage change in total daily insulin dose
- Percentage change in bodyweight
- Amount of carbohydrates and calories consumed after hypoglycemia
HbA1c levels
- Genitourinary adverse effects during treatment periods
- Occurrence of diabetic ketoacidosis |
- Respons van de contraregulerende hormonen ((nor)adrenaline, glucagon,
cortisol en groeihormoon) tijdens het hyperinsulinemische
hypoglykemische glucose clamp experiment
- Tijd tot herstel tot normoglykemie na afloop van de
hyperinsulinemische hypoglykemische glucose clamp
- Maximale glucosespiegel na afloop van de hyperinsulinemische
hypoglykemische glucose clamp
- Tijd tot maximale glucosepiek na afloop van de hyperinsulinemische
hypoglykemische glucose clamp
- Totale hyperglykemische belasting vanaf herstel tot normoglykemie
- Mate van hongergevoel na herstel van hypoglykemie
- Aantal ernstige hypoglykemieën tijdens 8 weken behandeling met
dapagliflozine of placebo
- Aantal nachtelijke hypoglykemieën tijdens 8 weken behandeling met
dapagliflozine of placebo
- Totaal aantal ernstige en niet-ernstige hypoglykemieën tijdens 8
weken behandeling met dapagliflozine of placebo
- Aantal hypoglykemieën en tijd in hypoglykemie gemeten met continue
glucose sensor registratie
- Glucosevariabiliteit gemeten met continue glucose sensor registratie
- Vitale kenmerken gemeten tijdens de hyperinsulinemiscpe
hypoglykemische glucose clamp
- Percentage verandering in totale dagelijkse insuline dosis
- Percentage verandering in lichaamsgewicht
- Hoeveelheid koolhydraten en calorieën geconsumeerd na hypoglykemie
- HbA1c waarde
- Frequentie van genitale of urineweginfecties
- Frequentie van diabetische ketoacidose
- Inflammatoire en atherogene fenotype van circulerende monocyten |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
During 8 weeks follow-up or during the hypoglycemic glucose clamp after 8 weeks of treatment |
Tijdens de 8 weken behandeling of gedurende de hypoglykemische glucose clamp na 8 weken behandeling |
|
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 | No |
E.6.5 | Efficacy | No |
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 | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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
|
LVLS |
Laatste visite van de laatste patiënt |
|
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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |