| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
Metabolic disease in which a person has high blood sugar because the
body does not produce enough insulin |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| 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 liraglutide as add on to intensive insulin treatment on the change of EGP during a hypoglycaemic clamp in C-peptide positive subjects with type 1 diabetes mellitus |
|
| E.2.2 | Secondary objectives of the trial |
To investigate the effect of liraglutide as add on to intensive insulin treatment on
Mixed Meal Tolerance Test(MMTT) enriched with Paracetamol:
• Change of gastric emptying during a MMTT assessed before firstdosing and after three months of liraglutide treatment compared to placebo
• glucagon and C-peptide response after during MMTT enriched with paracetamol before first dosing of liraglutide and after three months treatment
Hypoglycaemic Clamp:
• the change of peripheral glucose uptake
• the area under glucose infusion rate curve
• the glucagon response
• lactate, free fatty acids and glycerol levels
• the counterregulatory hormone levels
Clinical 3 months treatment:
• the glucagon levels
• the change of beta cell function
• the HbA1c and fasting plasma glucose (PG) levels
• the daily insulin treatment dose
• the change in body weight
• frequency and type of self-reported hypoglycaemic episodes
• the number and function of regulatory T-cells (Tregs) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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. Type 1 diabetes mellitus as diagnosed (including I - III):
I. history of type 1 diabetes mellitus manifestation with acute hyperglycaemia and ketonuria
II. positive results for at least one of four islet antibodies (glutamic acid decarboxy-lase, protein tyrosine phosphatase, zinc transporter 8, or islet cell antibodies)
III. residual basal fasting C-peptide of ≥ 0.1 nmol/L
3. Male or female, aged 18 – 64 years (both inclusive)
4. Body mass index (BMI) 19.0 - 28.0 kg/m2 (both inclusive)
5. HbA1c ≤ 80 mmol/mol (≤ 9.5%)
6. Treated with daily insulin injections or continuous s.c. insulin infusion (CSII) ≥ 1 months. Stable insulin dose as judged by the investigator
7. Able and willing to perform self-monitoring of PG according to the protocol, to keep a diabetes diary and willing to use liraglutide pen-device |
|
| E.4 | Principal exclusion criteria |
1. Known or suspected hypersensitivity to trial product(s) or related products
2. Use of liraglutide or exenatide within 3 months before screening
3. Recurrent severe hypoglycaemia (more than 1 severe hypoglycaemic event during the last 3 months)
4. Severe hypoglycaemia within 1 month of screening
5. Hypoglycaemia unawareness as judged by the Investigator or hospitalisation for dia-betic ketoacidosis during the previous 2 months
6. Clinically significant abnormal haematology, biochemistry, lipids, or urinalysis or coagulation screening tests, as judged by the investigator and any of the following laboratory safety results:
• ASAT, ALAT, lipase, alkaline phosphatase > 2.0 times upper limit of reference range (ULN)
• 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)
• Amylase above normal range
7. Screening calcitonin > 50 ng/L
8. Family or personal history of multiple endocrine neoplasia type 2 (MEN2), or family history of medullary thyroid cancer (MTC)
9. Personal history of non-familial medullary thyroid carcinoma
10. History of chronic or idiopathic acute pancreatitis
11. Suffer from or history of a life threatening disease (e.g. cancer except basal cell skin cancer or squamous cell skin cancer), or any clinically significant respiratory, meta-bolic, renal, hepatic, gastrointestinal, endocrinological (with the exception of diabetes mellitus and euthyroid struma), haematological, dermatological, venereal, neurological, psychiatric diseases or other major disorders as judged by the investigator.
12. Cardiac problems defined as decompensated heart failure (New York Heart Associa-tion (NYHA) class III and IV) at any time and/or angina pectoris within the last 12 months prior to screening and/or acute myocardial infarction at any time.
13. Supine blood pressure at screening (after resting for 5 min) outside the range of 90140 mmHg for systolic or 5090 mmHg for diastolic (repeated measurement on a second screening Visit allowed to exclude white-coat hypertension). This exclusion criterion also pertains to subjects being on antihypertensives.
14. Clinically significant abnormal ECG at screening, as judged by the investigator.
15. Proliferative retinopathy or maculopathy and/or severe neuropathy, in particular auto-nomic neuropathy, as judged by the investigator.
16. Any disease or condition that, in the opinion of the investigator, would represent an unacceptable risk for the subject’s safety.
17. Subject positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C antibodies (or diagnosed with active hepatitis according to local practice).
18. Positive result of the screening test for HIV-1 antibodies, HIV-2 antibodies and/or HIV-1 antigen according to locally used diagnostic testing.
19. History of multiple and/or severe allergies to drugs or foods or a history of severe ana-phylactic reaction.
20. Subject who has donated any blood or plasma in the past month or more than 500 mL within 3 months prior to screening.
21. Surgery or trauma with significant blood loss (more than 500 mL) within the last 3 months prior to screening.
22. Current treatment with systemic (oral or i.v.) corticosteroids, MAO inhibitors, non-selective beta-blockers, growth hormone, herbal products or non-routine vitamins. Fur-thermore, thyroid hormones are not allowed unless the use of these has been stable during the past month prior to screening.
23. Significant history of alcoholism or drug/chemical abuse as per investigator’s judge-ment or a positive result in the drug/alcohol screen at the screening Visit.
24. Smoker (defined as a subject who is smoking more than 5 cigarettes or the equivalent per day)
25. Not able or willing to refrain from smoking and use of nicotine gum or transdermal nicotine patches during the inpatient period.
26. Subject with mental incapacity or language barriers precluding adequate un-derstanding or co operation or who, in the opinion of the investigator, should not participate in the trial.
27. Potentially non-compliant or uncooperative during the trial, as judged by the investiga-tor.
28. Any condition that would interfere with trial participation or evaluation of results, as judged by the investigator.
29. Female of child-bearing potential who is pregnant, breast-feeding or intend to become pregnant or is not using adequate contraceptive methods (adequate contraceptive methods include sterilisation, hormonal intrauterine devices, oral contraceptives, sexual abstinence or vasectomised partner).
30. Use of drugs, which may interfere with the interpretation of trial results or are known to cause clinically relevant interference with insulin action, glucose utilisation, or recovery from hypoglycaemia
31. Severe acute and/or chronic diseases
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Area under the curve of endogenous glucose production (AUCEGP) from begin of 5.5 mmol/L period until end of recovery period (4.0 mmol/L), calculated from stable isotope labelled plasma glucose (PG) (labelled PG).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of each period
(Period 1: After 3 months)
(Period 2: After 7 months) |
|
| E.5.2 | Secondary end point(s) |
1.)Mixed Meal Tolerance Test with paracetamol:
The following endpoints relate to the MMTT with paracetamol before first dosing and after 3 months of treatment:
• Area under the glucose curve above the average baseline glucose value (average of the -5 and 0 min values) from time point 0 until 240 min during MMTT (AUCglu)
• Area under the C-peptide concentration curve (AUCC-peptide) from time point 0 until 120 min during MMTT
• Area under the C-peptide concentration curve (AUCC-peptide) from time point 0 until 240 min during MMTT
• C-peptide concentration at time point 90 min (C-Peptide90) during MMTT
• Area under the glucagon curve above the average baseline glucagon value (average of the -5 and 0 min values) from time point 0 until 240 min during MMTT (AUCglucagon)
• Mean glucagon and insulin concentration
• Gastric emptying calculated from the paracetamol concentrations as the area under the paracetamol concentration curve from time point 0 until 30 min (AUCpara30), time point 0 until 60 min (AUCpara60) time point 0 until 90 min (AUCpara90), from time point 0 until 120 min (AUCpara120), from time point 0 until 180 min (AUCpara180), and from time point 0 until 240 min (AUCpara240).
2.) Hypoglycaemic clamp:
The following endpoints relate to the whole period from begin of period 5.5mmol/L until end of recovery period (4.0 mmol/L)
• Area under the curve of peripheral glucose uptake (PGU), (AUCPGU) calculated from labelled PG.
• AUCGIR, area under the glucose infusion rate curve
The following endpoints are derived for each PG level (5.5, 3.5 and 2.5 mmol/L) during the hypoglycaemic clamp, and for the recovery phase (4.0mmol/L):
• EGP and PGU
• AUCGIR
• mean plasma glucagon concentrations; insulin/insulin secretion rate (if as-sessable), C-peptide
• mean values of adrenaline, noradrenaline, cortisol, growth hormone
• mean values of lactate, free fatty acids and glycerol
• time to reach each hypoglycaemic level (5.5, 3.5 and 2.2 mmol/L)
• change in pulse, systolic and diastolic blood pressure
• change in hypoglycaemic symptoms score (HSS)
• subjective hypoglycaemic awareness
In addition, the following endpoints relate to the recovery phase (4.0 mmol/L):
• TPG_nadir-4.0mmol/L, time from termination of insulin infusion at nadir (2.5mmol/L) to reach PG 4.0mmol/L
• AUCGIR, PG_nadir-4.0mmol/L, glucose infusion from termination of insulin infusion to reach PG 4.0mml/L
3.) Clinical 3 months treatment:
The following endpoints relate to before and after the 3-month treatment period, unless otherwise stated. Baseline is defined with Visit 2a for Period 1 and Visit 9a for Period 2:
• Change in HbA1c, and fasting PG
• Change in AUCC-peptide0-120, AUCC-peptide0-240, C-peptide90 from MMTT
• Change in mean glucagon and AUCglucagon
• Change in number and function of regulatory T-cells (Tregs)
• Change in daily insulin dose
• Change in 7-point glucose profile (mean plasma concentration, mean postprandial glucose increments)
4.) Safety Endpoints
• Number of treatment emergent adverse events
• Number of self-reported hypoglycaemic episodes (i.e. other than those investigated in the hypoglycaemic clamp setting) classified after ADA classification and time of hypo-glycaemia (nocturnal/day) during each period
• Change in pulse and blood pressure (systolic and diastolic), from baseline to end of treatment
• Shift in electrocardiogram (ECG) from baseline to end of treatment
• Change in physical examination from screening through follow-up
• Change in body weight from baseline to end of treatment
• Change in laboratory safety variables (clinical chemistry (including amylase and lipase, calcitonin), haematology, urinalysis)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.)Mixed Meal Tolerance Test with paracetamol
After the beginning and end of each period (1month, 3month, 5month, 7month)
2.) Hypoglycaemic clamp:
At the end of each period (3month, 7month)
3.) Clinical 3 months treatment
During each period (Period 1 and 2)
4.) Safety Endpoints
During the whole study (7months) |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 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 | |
| E.8.9.1 | In the Member State concerned months | 15 |
| E.8.9.1 | In the Member State concerned days | |
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