Identifying Potential Effects of Liraglutide on Degenerative Changes

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ClinicalTrials.gov Identifier: NCT01469351

Recruitment Status : Completed

First Posted : November 10, 2011

Last Update Posted : April 19, 2013

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

University of Aarhus

Study Description

Brief Summary:

Today Alzheimers disease can not be cured. Animal experiments have shown that the hormone GLP-1 can improve memory in Alzheimer-prone mice.

The investigators hypothesis is that a 6-month treatment with the GLP-1 receptor stimulating drug liraglutide will reduce the intracerebral amyloid deposition in the central nervous system (CNS) in patients with Alzheimer's disease (AD) and thereby reduce the clinical symptoms of the disease.

Condition or disease	Intervention/treatment	Phase
Alzheimers Disease	Drug: Liraglutide Drug: non-active study drug	Not Applicable

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Detailed Description:

The incidences of both type 2 diabetes (DM-2) and Alzheimer's disease (AD) have increased during the last years, resulting in an increase in morbidity and mortality. DM-2 is a risk factor for both AD and vascular dementia. In addition, an increased incidence of DM-2 in Alzheimer's patients has been observed. The understanding of the underlying mechanism behind this linkage is so far very sparse.

In both diseases premature cell degeneration develops. DM-2 is characterized by a loss of β-cell function and β cell mass in the pancreas, whereas AD shows a loss of neuronal function as well as neuronal cell death. General metabolic risk factors such as hyperglycemia and hypercholesterolemia are evident in both diseases.

Glucagon-like-peptide-1 (GLP-1) is an incretin hormone with numerous documented effects on the glycaemic response. It is released as a response to food ingestion and consequently exerts a glucose-dependent stimulation of insulin secretion while inhibiting glucagon secretion. In animal experiments as well as cell experiments β-cell neogenesis, growth and differentiation are stimulated by GLP-1, and inhibition of β-cell apoptosis has been demonstrated in cell studies. In addition to α- and β-cells of the pancreas, GLP-1 receptors (GLP-1R) have been localized to the CNS, where GLP-1R are distributed corresponding to the hypothalamus and hippocampus. Experimental investigations on mice where GLP-1 was given intra-cerebroventricularly, GLP-1R stimulation reduced nerve cell damage caused by neurotoxic stimuli. Furthermore, GLP-1R stimulation in hippocampus induced learning ability and memory and it has been shown that GLP-1R stimulation leeds to neurite outgrowth and protects against nerve cell apoptosis.

In connection with hyperinsulinaemia in early stages of DM-2, studies suggest that stimulation of insulin receptors represented in the brain produce an increased level of β-amyloid and an increased number of neurofibrillary tangles. AD is pathologically characterized by an increased level of β-amyloid as well as an increased number of neurofibrillar tangles. Accumulation of β-amyloid in the brain is localized to areas with cognitive functions. A recent animal experimental work has shown reduced memory in GLP-1 receptor KO mice and mentions the lack of a possible neuroprotective effect as a potential explanation for the observation. In studies of humans a worsening of the cognitive functions has been shown to be associated with dementia and DM-2, even though an actual causal relation has not yet been found. The investigators have recently shown that GLP-1 has a neuroprotective function in patients with DM-2.

Positron emission tomography (PET) scanning has been well evaluated in clinical demonstration of CNS changes following AD including changes in amyloid deposits.

Presently there are no registered drugs which change the deposition of amyloid and there are no drugs with convincing effect on the progression of the disease in patients with Alzheimer's. Moreover the drugs which have been marketed for treatment have a disadvantageous side effect profile. Besides insulin, β-cells secrete amylin, amyloid or IAPP (islet amyloid polypeptide) and these thus share certain characteristics with β-amyloid. Previously IAPP was considered to be non-toxic but recent studies have indicated a possible conversion to toxic β-amyloid.

The insulin-producing β-cells have been found to be characterized by accumulation of amyloid in several DM-2 models. A recent study with treatment with DPP-4 inhibitors (increasing endogenous GLP-1) improved glucose tolerance, increased GLP-1 levels and normalized the topography of the islets of Langerhans in a mouse model with β cell specific over expression of human amyloid.

The investigators hypothesis is that a 26 week treatment with the GLP-1 receptor stimulating pharmaceutical liraglutide will reduce the intracerebral amyloid deposition in the CNS in patients with Alzheimer's disease, as demonstrated by PET.

The investigators aim is that this clinical study will be able to give new information about the effect of the GLP-1 axis in the CNS and explore the potential for treatment of large groups of patients who cannot be offered effective drugs today. Altogether the results from the studies will contribute to the development of future treatment options for AD.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	34 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Neurodegenerative Changes in Alzheimer's Disease: Identifying Potential Effects of Liraglutide on Degenerative Changes
Study Start Date :	January 2012
Actual Primary Completion Date :	April 2013
Actual Study Completion Date :	April 2013

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Alzheimer disease

MedlinePlus related topics: Alzheimer's Disease

Drug Information available for: Liraglutide

Genetic and Rare Diseases Information Center resources: Familial Alzheimer Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Drug the GLP-1 receptor analog liraglutide is the active drug. The dose is 1.8mg daily	Drug: Liraglutide Liraglutide (Victoza ®), human GLP-1 analog produced using recombinant DNA technology in saccharomyces cerevisiae. Victoza ® is registered and approved for the treatment of type 2 diabetes. Victoza ® stimulates glucose-dependent insulin secretion from β-cells and inhibits glucagon secretion, slows ventricle emptying and reduces body weight and body fat mass by affecting appetite regulation. Form of administration: Liraglutide is a clear injection fluid, which comes in a prefilled disposable pen. 1 ml contains 6 mg of liraglutide in sterile water. There is added disodium phosphate and propylene glycol and the preservative phenol. A filled pen contains 18mg liraglutide in 3ml. NovoFine® needles are used.
Placebo Comparator: placebo non active intervention	Drug: non-active study drug placebo

Arm

Intervention/treatment

Active Comparator: Drug

the GLP-1 receptor analog liraglutide is the active drug. The dose is 1.8mg daily

Drug: Liraglutide

Liraglutide (Victoza ®), human GLP-1 analog produced using recombinant DNA technology in saccharomyces cerevisiae. Victoza ® is registered and approved for the treatment of type 2 diabetes.

Victoza ® stimulates glucose-dependent insulin secretion from β-cells and inhibits glucagon secretion, slows ventricle emptying and reduces body weight and body fat mass by affecting appetite regulation.

Form of administration: Liraglutide is a clear injection fluid, which comes in a prefilled disposable pen.

1 ml contains 6 mg of liraglutide in sterile water. There is added disodium phosphate and propylene glycol and the preservative phenol. A filled pen contains 18mg liraglutide in 3ml. NovoFine® needles are used.

Placebo Comparator: placebo

non active intervention

Drug: non-active study drug

placebo

Outcome Measures

Primary Outcome Measures :

PIB PET scan [ Time Frame: PIB PET-scan at baseline and after 26 weeks ]
Primarily to investigate whether 26 weeks of treatment with GLP-1 receptor liraglutide (Victoza ®) will change the intra-cerebral amyloid deposit in the CNS in patients with Alzheimer's disease assessed by PIB PET scan.

Secondary Outcome Measures :

Neuro-psychological tests [ Time Frame: At baseline, after 12 weeks and after 26 weeks ]
To validate the cognitive functions using specific neuro-psychological test battery before and after treatment with liraglutide/placebo.
FDG PET Scan [ Time Frame: FDG PET-scan at baseline and after 26 weeks ]
To examine changes in glucose uptake in the CNS by FDG PET scan before and after 6 months of treatment with liraglutide/placebo

Eligibility Criteria

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Ages Eligible for Study:	50 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Informed consent before study-related activity
Adult competent persons
Diagnosed with diagnosed Alzheimer's disease. With a MMSE score between 18-21 the diagnosis should be entirely based on the clinic, while diagnosis by MMSE with a score > 22 should be diagnosed by spinal puncture
Age ≥ 50 years and ≤ 80 years
Caucasians

Exclusion Criteria:

Diabetes mellitus
Clinically significant liver (s-ALT > 2 times upper reference or creatinine-clearance < 30 mL / min, assessed on Cockcroft-Gault normogram)
Clinically significant anemia
Other clinically relevant abnormal biochemical value
Current or former presence of one of the following diseases with clinical relevance:
1. another CNS-illness other than diagnosed depression treated with SSRI or SSRI similar drugs.
2. liver disease
3. kidney disease
4. endocrinological disease other than well controlled hypothyroidism
Current or history of chronic or acute pancreatitis
Any disease which the investigators believe may affect the study
Patients treated with TCA or neuroleptics
Known abuse of alcohol or drugs
Known allergy to liraglutide or any of the other components (disodium phosphate dihydrate, propylene glycol and phenol)
Participation in a clinical trial less than 3 months before inclusion in this study
Persons who within a period of the last 2 years have participated in scientific experiments involving the use of isotopes, or who have had greater diagnostic tests performed using applied ionizing radiation
If patients are treated with SSRI or SSRI similar drugs or antihypertensives this treatment should be stable
Claustrophobia or other missing cooperation
Severe overweight > 130kg
Ferro-magnetic prosthesis, pacemaker or other metals incorporated in the body
Significant abnormities in the brain detected by MR scanning

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01469351

Locations

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Denmark
Aarhus University
Aarhus, Denmark, 8000

Sponsors and Collaborators

University of Aarhus

Investigators

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Principal Investigator:	Birgitte Brock, MD phD	University of Aarhus

More Information

Additional Information:

information about Alzheimers disease This link exits the ClinicalTrials.gov site

Publications:

Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease. Behav Brain Res. 2009 Dec 14;205(1):265-71. doi: 10.1016/j.bbr.2009.06.035. Epub 2009 Jun 30.

Cole AR, Astell A, Green C, Sutherland C. Molecular connexions between dementia and diabetes. Neurosci Biobehav Rev. 2007;31(7):1046-63. doi: 10.1016/j.neubiorev.2007.04.004. Epub 2007 Apr 24.

Dimou E, Booij J, Rodrigues M, Prosch H, Attems J, Knoll P, Zajicek B, Dudczak R, Mostbeck G, Kuntner C, Langer O, Bruecke T, Mirzaei S. Amyloid PET and MRI in Alzheimer's disease and mild cognitive impairment. Curr Alzheimer Res. 2009 Jun;6(3):312-9. doi: 10.2174/156720509788486563.

During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003 Sep;9(9):1173-9. doi: 10.1038/nm919. Epub 2003 Aug 17.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. doi: 10.1016/j.tem.2016.10.001. Epub 2016 Oct 27.

Gejl M, Gjedde A, Egefjord L, Moller A, Hansen SB, Vang K, Rodell A, Braendgaard H, Gottrup H, Schacht A, Moller N, Brock B, Rungby J. In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci. 2016 May 24;8:108. doi: 10.3389/fnagi.2016.00108. eCollection 2016.

Egefjord L, Gejl M, Moller A, Braendgaard H, Gottrup H, Antropova O, Moller N, Poulsen HE, Gjedde A, Brock B, Rungby J. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease - protocol for a controlled, randomized double-blinded trial. Dan Med J. 2012 Oct;59(10):A4519.

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Responsible Party:	University of Aarhus
ClinicalTrials.gov Identifier:	NCT01469351
Other Study ID Numbers:	2011-000794-31
First Posted:	November 10, 2011 Key Record Dates
Last Update Posted:	April 19, 2013
Last Verified:	April 2013

Keywords provided by University of Aarhus:


Alzheimers disease

Additional relevant MeSH terms:

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Alzheimer Disease Dementia Brain Diseases Central Nervous System Diseases Nervous System Diseases Tauopathies Neurodegenerative Diseases Neurocognitive Disorders	Mental Disorders Liraglutide Hypoglycemic Agents Physiological Effects of Drugs Incretins Hormones Hormones, Hormone Substitutes, and Hormone Antagonists

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