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Long-acting Exenatide and Cognitive Decline in Dysglycemic Patients (DRINN)

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ClinicalTrials.gov Identifier: NCT02847403
Recruitment Status : Recruiting
First Posted : July 28, 2016
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Alessandra Dei Cas, Azienda Ospedaliero-Universitaria di Parma

Brief Summary:
The overall objective of the study is to assess the potential effects of the long-acting GLP-1 analogue exenatide in preventing/slowing the progression of cognitive dysfunction and related biomarkers in dysglycemic/prediabetic patients with mild cognitive impairment (MCI).

Condition or disease Intervention/treatment Phase
Dysglycemia Cognitive Deficit Drug: Exenatide Other: placebo Phase 3

Detailed Description:

Type 2 Diabetes Mellitus (T2DM) and Alzheimer's Disease (AD) are two of the most common diseases of aging.The presence of T2DM almost doubles the risk of developing AD and is associated with a faster rate of cognitive decline in those with mild cognitive impairment (MCI). Blood glucose levels are directly associated with accelerated cognitive decline also in subjects with impaired fasting glucose and in individuals without clinical DM. Impaired insulin signaling is critically involved in the natural history of both T2DM and AD and it may represent a common mechanistic link ("common soil") between dysglycemic/prediabetic states and AD development and progression.

The overall objective of the study is to assess the potential effects of the long-acting GLP-1 analogue exenatide in preventing/slowing the progression of cognitive dysfunction and related biomarkers in dysglycemic/prediabetic patients with mild cognitive impairment (MCI).

All eligible patients at V0 will undergo baseline assessments (V1) and will be allocated according to the procedure of randomization to one of the study arms. Follow-up (FU) visits for all subjects will be at 16 (V2) and at 32 weeks (V3) after randomization. Additionally, subjects on active treatment will be admitted weekly to the Outpatient Diabetes Unit of the AOUPR for GLP-1 subcutaneous injections and to check for possible side effects. Subjects in the control arm will be seen at the Center for Dementia (AOUPR) according to their usual schedule.

Laboratory and diagnostic:

At each study visits patients will undergo:

  • anthropometric and hemodynamic assessment: weight and height for Body Mass Index (BMI) calculation, waist circumference, ambulatory blood pressure, heart rate;
  • blood test collection of metabolic profile: blood collection for metabolic/hormonal profile: fasting plasma glucose, HbA1c, insulin, C-peptide, glucagon, active GLP-1, total gastric inhibitory polypeptide (GIP), total cholesterol, HDL-cholesterol, triglycerides, AST, ALT, pancreatic amylase, lipase, creatinine, eGFR.
  • cognitive function tests: ADAS-cog and the quality score of MMSE, Phonemic verbal fluency test; Semantic verbal fluency test; Geriatric Depression Scale (GDS) ; Clinical Dementia Rating Scale (CDR); Neuropsychiatric Inventory (NPI); Activities of Daily Living (ADL); Instrumental Activities of Daily Living (IADL).

ADAS-cog was designed to measure the severity of the most important symptoms of Alzheimer's disease. It consists of 11 7 tasks measuring the disturbances of memory, language, praxis, attention and other cognitive abilities which are often referred to as the core symptoms of AD.

- Functional Magnetic Resonance Imaging (MRI)(only at V1 and V3).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Long-acting Exenatide: a Tool to Stop Cognitive Decline in Dysglycemic Patients With Mild Cognitive Impairment?
Study Start Date : February 2016
Actual Primary Completion Date : July 2019
Estimated Study Completion Date : October 31, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Exenatide

Arm Intervention/treatment
Experimental: exenatide
long-acting exenatide 2 mg subcutaneously once-weekly
Drug: Exenatide
Patients will be injected subcutaneously 2 mg long-acting exenatide once-weekly. No dose titration is foreseen.
Other Name: bydureon

Placebo Comparator: placebo
no drug assigned
Other: placebo
patients will be seen at the Center for Cognitive Disorders and Dementia according to their usual schedule.




Primary Outcome Measures :
  1. Improvement of ADAS-cog Alzheimer's Disease Assessment Scale defined by ADAS-cog score at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the ADAS-Cog score compared to baseline in the 2 arms.


Secondary Outcome Measures :
  1. Improvement of Mini Mental State Evaluation test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the Mini Mental State Evaluation (MMSE) score compared to baseline in the 2 arms.

  2. Improvement of Mini Mental State Evaluation quality test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the MMSE quality test score compared to baseline in the 2 arms.

  3. Improvement of Phonemic verbal fluency test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the Phonemic verbal fluency test score compared to baseline in the 2 arms.

  4. Improvement of Semantic verbal fluency test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the Semantic verbal fluency test score compared to baseline in the 2 arms.

  5. Improvement of Geriatric Depression Scale (GDS) test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the GDS test score compared to baseline in the 2 arms.

  6. Improvement of Clinical Dementia Rating Scale (CDR) test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the CDR test score compared to baseline in the 2 arms.

  7. Improvement of Neuropsychiatric Inventory (NPI) test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the NPI test score compared to baseline in the 2 arms.

  8. Improvement of Activities of Daily Living (ADL) test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the ADL test score compared to baseline in the 2 arms.

  9. Improvement of Instrumental Activities of Daily Living (IADL) test at 16 (V2) and at 32 weeks (V3) compared to baseline [ Time Frame: 16 and 32 weeks ]
    Absolute difference in the IADL test score compared to baseline in the 2 arms.

  10. changes in structural and functional connectivity of neural networks as assessed by functional MRI (fMRI) at 16 (V2) and at 32 weeks (V3) [ Time Frame: 16 and 32 weeks ]
    Before and after treatment voxel-wise brain maps will be statistically compared using Statistical Parametric Mapping, by a multivariate 2 x 2 ANOVA (experimental treatment /placebo x time pre/post) in order to observe changes in structural and functional connectivity of neural networks in relation to treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   51 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patients capable of giving informed consent
  • dysglycemia/prediabetes defined as fasting plasma glucose between 100 and 125 mg/dl and/or 2-hour plasma glucose between 140 and 199 mg/dl after a 75 g OGTT and/or a HbA1c value between 5.7 and 6.4%
  • diagnosis of MCI according to the Petersen clinical criteria (the expected corrected scores at the MMSE are from 24 to 27)
  • age >50<80 yrs
  • stable medication for the past 3 months
  • Caucasian ethnicity

Exclusion Criteria:

  • age <50>80 yrs
  • incapability to give informed consent
  • diabetes defined according to American Diabetes Association (ADA) criteria
  • clinically significant liver or kidney dysfunction defined as s-ALT > 2 times upper reference or estimated creatinine-clearance (eGFR) < 60 mL / min/1.73m2, assessed by with CKD-EPI formula
  • endocrinological diseases other than well controlled hypothyroidism, personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia (MEN) syndrome, severe gastro-intestinal diseases (i.e gastroparesis, dumping syndromes), current or history of chronic or acute pancreatitis
  • any contraindication to the use of exenatide as per the Summary of Product Characteristics
  • known abuse of alcohol or drugs
  • ferro-magnetic prosthesis, pacemaker or other metals incorporated in the body
  • significant neurologic disease other than MCI (i.e. Parkinson's disease, multiple system atrophy, normal pressure hydrocephalus, progressive supranuclear palsy, subarachnoid hemorrhage, brain neoplasms, Huntington disease, epilepsy or head trauma)
  • BMI ≤22 Kg/m2 in subject ≥ 70 yrs
  • MRI/CT showing unambiguous etiological evidence of cerebrovascular disease with regard to MCI
  • severe sensory defects; current presence of clinically significant psychiatric disorder
  • warfarin treatment, clinically significant systemic condition
  • history of cancer within the last 5 yrs
  • known allergy to exenatide or any of the other components.

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): NCT02847403


Contacts
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Contact: Alessandra Dei Cas, MD 00390521033321 alessandra.deicas@unipr.it

Locations
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Italy
Endocrinology Unit Recruiting
Parma, Italy, 43126
Contact: Alessandra Dei Cas, MD, PhD         
Sub-Investigator: Paolo Caffarra, MD         
Center for Cognitive Disorders and Dementia AUSL of Parma and University of Parma Recruiting
Parma, Italy
Contact: Paolo Caffarra, MD         
Sponsors and Collaborators
Azienda Ospedaliero-Universitaria di Parma
Investigators
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Principal Investigator: Alessandra Dei Cas, MD Azienda Ospedaliero-Universitaria di Parma

Publications:
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Responsible Party: Alessandra Dei Cas, Research Assistant, MD, PhD, Azienda Ospedaliero-Universitaria di Parma
ClinicalTrials.gov Identifier: NCT02847403    
Other Study ID Numbers: 2015-001850-13
First Posted: July 28, 2016    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by Alessandra Dei Cas, Azienda Ospedaliero-Universitaria di Parma:
dysglycemia
MCI
exenatide LAR
GLP-1
Additional relevant MeSH terms:
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Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Exenatide
Hypoglycemic Agents
Physiological Effects of Drugs
Anti-Obesity Agents
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists