Treatment of Diabetic Neuropathy With Liraglutide (TODINELI)

A Randomized, Double-blinded, Single-centre, Parallel-group, Placebo-controlled, Prospective Trial of Neuroprotective Effect of Liraglutide for Treatment of Diabetic Neuropathy.

The purpose of this trial is to explore whether liraglutide has a long term effect on clinical symptoms and biomarkers in patients with diabetic neuropathy.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1; Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo treatment; Drug: Liraglutide treatment

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Jutland
    • Aalborg, Jutland, Denmark, 9000
      • Mech-Sense, Department of Medical Gastroenterology, Aalborg University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Abile person of Northern European descent
• Age between 18 to 65 years
• A verified diagnosis of DM type 1 for minimum 2 years (HbA1C=7%)
• Stable DM treatment (Treatment is considered stable when the patient has been treated with basal-bolus insulin, premixed insulin or continously infused insulin with an insulin dose considered stable by investigator for at least 3 months prior to screening.)
• The participants must be able to read and understand Danish.
• Peripheral diabetic neuropathy ensured by having abnormal nerve conduction velocity
• BMI equal to or above 22
• Personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.
• Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other trial procedures.

Exclusion Criteria:

• Diabetes mellitus type II
• Estimated glomerular filtration rate (s-creatinin/eGRF) < 60 ml/min/1.37m2
• Calcitonin > 25
• HbA1c level < 7%
• 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.
• Patients on GLP-1 receptor agonist treatment (exenatide, liraglutide or others) or pramlintide or any DPP-4 inhibitor within 3 months prior to screening.
• Other neurological and/or psychiatric disease
• Treatment of other endocrinological disease except hypothyreosis
• Malignant neoplasms requiring chemotherapy, surgery, radiation or palliative care in the previous 5 years.
• Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma.
• Personal history of non-familial medullary thyroid carcinoma
• Known abuse or alcohol and/or medicine (Alcohol use in accordance with the recommendations by the Danish Health and Medicines Authority are allowed).
• Known allergy to liraglutide.
• Participation in other clinical trials less than 3 months prior to inclusion
• Female patients who are pregnant or lactating, or intend to become pregnant and male patients who intend to father a child during course of the study.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo treatment; Placebo solution will be slowly titrated to maximum tolerable dose in order to minimize potential side-effects, hence treatment will follow: First and second week: 0.6 mg/day; Third and fourth week: 1.2 mg/day and Fifth and to sixth week: 1.8 mg/day.	Drug: Placebo treatment; Treatment continues at highest tolereable dose (minimum 1.2 mg/day). Intervention time 26 weeks at target dose.
ACTIVE_COMPARATOR: Liraglutide treatment; Liraglutide will be slowly titrated to maximum tolerable dose in order to minimize potential side-effects, hence treatment will follow: First and second week: 0.6 mg/day; Third and fourth week: 1.2 mg/day and Fifth and to sixth week: 1.8 mg/day.	Drug: Liraglutide treatment; Treatment continues at highest tolereable dose (minimum 1.2 mg/day). Intervention time 26 weeks at target dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
RIII withdrawal reflex activity (using standard electromyography)	After 6 months of treatment with Liraglutide
Evoked brain potentials (using standard electroencephalographic brain imaging).	After 6 months of treatment with Liraglutide

Secondary Outcome Measures

Outcome Measure	Time Frame
Heart rate variability/ alterations in simpatico-vagal balance (24 h Holter monitoring)	After 6 months of treatment with Liraglutide
Resting brain activity (spectral analysis of resting brain activity)	After 6 months of treatment with Liraglutide
Microstructural brain neurodegeneration (assessed by diffuse tensor imaging)	After 6 months of treatment with Liraglutide
Variety in day/night blood pressure	After 6 months of treatment with Liraglutide
Gut transit assessed by SmartPill (pH, pressure and transit in stomach, small and large intestine)	After 6 months of treatment with Liraglutide
Quantitive sensory testing of pressure algometry in muscle	After 6 months of treatment with Liraglutide
Capacity of descending pain inhibition induced by a cold pressor test (2C in 120 sec)	After 6 months of treatment with Liraglutide
Profile of inflammatory cytokines including IL-beta, TNF-alfa, IL6, MCP-1 and specific markers sCD163, sMR, neopterin and HO-1.	After 6 months of treatment with Liraglutide
Metabolic risk factors expressed as adipokines (adiponectin, leptin, resistin) and inflammatory cell markers	After 6 months of treatment with Liraglutide
Self assessed symptomatology (Michigan neuropathy screening tool, Quality of life (SF-36), Pain catastrophizing scale (PCS) and self-assessed gastro-intestinal symptoms (PAGI-SYM))	After 6 months of treatment with Liraglutide
OCT	After 6 months of treatment with Liraglutide

Other Outcome Measures

Outcome Measure	Time Frame
HbA1C	After 6 months of treatment with Liraglutide
Biochemical lipid profile	After 6 months of treatment with Liraglutide
Heart rate and blood pressure	After 6 months of treatment with Liraglutide
Weight/body mass index	After 6 months of treatment with Liraglutide

Collaborators and Investigators

• Sponsor: Aalborg University Hospital
• Collaborators: Novo Nordisk A/S
• Investigators: Principal Investigator: Asbjørn M. Drewes, Professor, Mech-Sense, Department of Medical Gastroenterology, Aalborg Hospital

Publications and helpful links

General Publications

• Arendt Nielsen T, Sega R, Uggerhoj Andersen C, Vorum H, Drewes AM, Jakobsen PE, Brock B, Brock C. Liraglutide Treatment Does Not Induce Changes in the Peripapillary Retinal Nerve Fiber Layer Thickness in Patients with Diabetic Retinopathy. J Ocul Pharmacol Ther. 2022 Jan-Feb;38(1):114-121. doi: 10.1089/jop.2021.0055. Epub 2021 Dec 16.
• Nissen TD, Meldgaard T, Nedergaard RW, Juhl AH, Jakobsen PE, Karmisholt J, Drewes AM, Brock B, Brock C. Peripheral, synaptic and central neuronal transmission is affected in type 1 diabetes. J Diabetes Complications. 2020 Sep;34(9):107614. doi: 10.1016/j.jdiacomp.2020.107614. Epub 2020 May 8.
• Nedergaard RB, Nissen TD, Morch CD, Meldgaard T, Juhl AH, Jakobsen PE, Karmisholt J, Brock B, Drewes AM, Brock C. Diabetic Neuropathy Influences Control of Spinal Mechanisms. J Clin Neurophysiol. 2021 Jul 1;38(4):299-305. doi: 10.1097/WNP.0000000000000691.
• Brock C, Hansen CS, Karmisholt J, Moller HJ, Juhl A, Farmer AD, Drewes AM, Riahi S, Lervang HH, Jakobsen PE, Brock B. Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy. Br J Clin Pharmacol. 2019 Nov;85(11):2512-2523. doi: 10.1111/bcp.14063. Epub 2019 Aug 30.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (ACTUAL): February 1, 2017
• Study Completion (ACTUAL): February 1, 2017

Study Registration Dates

• First Submitted: May 13, 2014
• First Submitted That Met QC Criteria: May 13, 2014
• First Posted (ESTIMATE): May 14, 2014

Study Record Updates

• Last Update Posted (ACTUAL): August 10, 2021
• Last Update Submitted That Met QC Criteria: August 9, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Liraglutide; Diabetic Neuropathy; Diabetes Mellitus, Type 1
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Complications; Neuromuscular Diseases; Peripheral Nervous System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: TODINELI