E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
TODINELI Trial A randomized, double-blinded, single-centre, parallel-group, placebo-controlled, prospective trial of the neuroprotective effect of Liraglutide for treatment of diabetic neuropathy in Diabets mellitus type I patients |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of diabetes neuropathy with liraglutide |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012685 |
E.1.2 | Term | Diabetic polyneuropathy |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012682 |
E.1.2 | Term | Diabetic peripheral autonomic neuropathy |
E.1.2 | System Organ Class | 100000004852 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012683 |
E.1.2 | Term | Diabetic peripheral neuropathy |
E.1.2 | System Organ Class | 100000004852 |
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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 |
Type I Diabetes mellitus The present study is an experimental setup, where we want to explore the neuroprotective effect of liraglutide in controlled and standardized experimental neurophysiological pain models. |
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E.2.2 | Secondary objectives of the trial |
In addition, basic pain mechanisms in diabetic neuropathy will be explored as these findings may predict clinical efficacy of liraglutide, based on the patient baseline profile prior to treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Habile person of Northern European descent 2) Age between 18 to 65 years 3) A verified diagnosis of DM type I for minimum 2 years 4) Stable DM treatment for minimum 3 months prior to screening 5) The participants must be able to read and understand Danish. 6) Peripheral diabetic neuropathy ensured by having abnorm nerve conduction velocity 7) BMI equal to or above 22 8) Personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial. 9) Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other trial procedures. |
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E.4 | Principal exclusion criteria |
1) Estimated glomerular filtration rate (s-creatinin/eGFR ) < 60 ml/min/1.37m2 2) Calcitonin > 25) 3) HbA1c level < 7% 4) Patients with any clinically significant laboratory abnormalities, that in the opinion of the investigator may increase the risk associated with trial participation or may interfere with the interpretation of the trial results. 5) Patients on GLP-1 receptor agonist treatment (exenatide, liraglutide or others) or pramlintide or any DPP-4 inhibitor within 3 months prior to screening. 6) Other neurological and/or psychiatric disease 7) Treatment of other endocrinological disease except hypothyreosis 8) Malignant neoplasms requiring chemotherapy, surgery, radiation or palliative care in the previous 5 years. 9) Family or personal history of multiple endocrine neoplasis type 2 (MEN2) or familial medullary thyroid carcinoma 10) Personal history of non-familial medullary thyroid carcinoma 11) Known abuse of alcohol and/or medicine (Alcohol use in accordance with the recommendations by the Danish Health and Medicines Authority are allowed). 12) Known allergy to liraglutide 13) Participation in other clinical trials less than 3 months prior to inclusion 14) Female patients who are pregnant or lactating, or intend to become pregnant and male patients who intend to father a child during the course of the study. 15) In women, a serum pregnancy test will be conducted at baseline based on h-CG in the blood. The investigator will have to ensure that fertile female patients use a safe contraception method during the study and for at least 15 hours after termination of the study medication period. The following methods are considered as safe contraception methods: a. The combined oral contraceptive pill b. Intra uterine device c. Gestagen injection d. Subdermal implantation e. Hormone vaginal ring f. Transdermal plaster |
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E.5 End points |
E.5.1 | Primary end point(s) |
Alterations in the electrophysiological profile assessed by 1) RIII withdrawal reflex activity (using standard electromyography) and 2) Evoked brain potentials (using standard electroencephalographic brain imaging). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
before and after 26 weeks of intervention |
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E.5.2 | Secondary end point(s) |
Alterations in: 1) Heart rate variability/ alterations in the simpatico-vagal balance; (24 h Holter monitoring) 2) Resting brain activity; (spectral analysis of resting brain activity) 3) Microstructural brain neurodegeneration (assessed by diffuse tensor imaging) 4) Variety in day/night blood pressure; 5) Gut transit assessed by SmartPill; (pH, pressure and transit in stomach, small and large intestine) 6) Quantitive sensory testing of pressure algometry in muscle 7) Capacity of descending pain inhibition induced by a cold pressor test (2°C water in 120 sec) 8) Profile of inflammatory cytokines including IL1β, TNF-α, IL6, MCP-1 and specific macrophage markers sCD163, sMR, neopterin and HO-1. 9) Alteration of edema in retina |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Before and after 26 weeks of intervention |
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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 | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
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 | 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 | |
E.8.9.1 | In the Member State concerned days | |