DRINN: Long-acting Exenatide and Cognitive Decline in Dysglycemic Patients

Sponsor

Azienda Ospedaliero-Universitaria di Parma (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02847403

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

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).

Study Design

Study Type:

Interventional

Anticipated 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 :

Feb 1, 2016

Actual Primary Completion Date :

Jul 1, 2019

Anticipated Study Completion Date :

Oct 31, 2021

Arms and Interventions

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 Names: 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.

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 Names:

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.

Outcome Measures

Primary Outcome Measures

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 [16 and 32 weeks]
Absolute difference in the ADAS-Cog score compared to baseline in the 2 arms.

Secondary Outcome Measures

Improvement of Mini Mental State Evaluation test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the Mini Mental State Evaluation (MMSE) score compared to baseline in the 2 arms.
Improvement of Mini Mental State Evaluation quality test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the MMSE quality test score compared to baseline in the 2 arms.
Improvement of Phonemic verbal fluency test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the Phonemic verbal fluency test score compared to baseline in the 2 arms.
Improvement of Semantic verbal fluency test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the Semantic verbal fluency test score compared to baseline in the 2 arms.
Improvement of Geriatric Depression Scale (GDS) test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the GDS test score compared to baseline in the 2 arms.
Improvement of Clinical Dementia Rating Scale (CDR) test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the CDR test score compared to baseline in the 2 arms.
Improvement of Neuropsychiatric Inventory (NPI) test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the NPI test score compared to baseline in the 2 arms.
Improvement of Activities of Daily Living (ADL) test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the ADL test score compared to baseline in the 2 arms.
Improvement of Instrumental Activities of Daily Living (IADL) test at 16 (V2) and at 32 weeks (V3) compared to baseline [16 and 32 weeks]
Absolute difference in the IADL test score compared to baseline in the 2 arms.
changes in structural and functional connectivity of neural networks as assessed by functional MRI (fMRI) at 16 (V2) and at 32 weeks (V3) [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

51 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.