Identifying Potential Effects of Liraglutide on Degenerative Changes

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Aarhus
ClinicalTrials.gov Identifier:
NCT01469351
First received: November 1, 2011
Last updated: April 18, 2013
Last verified: April 2013
  Purpose

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 Intervention
Alzheimers Disease
Drug: Liraglutide
Drug: non-active study drug

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Neurodegenerative Changes in Alzheimer's Disease: Identifying Potential Effects of Liraglutide on Degenerative Changes

Resource links provided by NLM:


Further study details as provided by University of Aarhus:

Primary Outcome Measures:
  • PIB PET scan [ Time Frame: PIB PET-scan at baseline and after 26 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    To examine changes in glucose uptake in the CNS by FDG PET scan before and after 6 months of treatment with liraglutide/placebo


Enrollment: 34
Study Start Date: January 2012
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   50 Years to 80 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01469351

Locations
Denmark
Aarhus University
Aarhus, Denmark, 8000
Sponsors and Collaborators
University of Aarhus
Investigators
Principal Investigator: Birgitte Brock, MD phD University of Aarhus
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT01469351     History of Changes
Other Study ID Numbers: 2011-000794-31
Study First Received: November 1, 2011
Last Updated: April 18, 2013
Health Authority: Denmark: Danish Medicines Agency

Keywords provided by University of Aarhus:
Alzheimers disease

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Glucagon-Like Peptide 1
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 23, 2014