A Novel Therapeutic Target for Alzheimer's Disease in Men and Women 50-85 Years of Age.

Mild Cognitive Impairment Clinical Trial

Official title:

A 24-month, Randomized-control, Double-blind, Multi-center, Delayed-start, Pilot Study Evaluating Thrombin Inhibitions Alzheimer's Disease Using 150mg Dabigatran Daily: A Novel Therapeutic Target for Alzheimer's Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03752294
• Other study ID #: RIN001-001
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: November 2018
• Est. completion date: December 2021

Study information

• Verified date: November 2018
• Source: University of Rhode Island
• Contact: Chris Getter
• Phone: 401-874-2358
• Email: cgetter[@]uri.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A randomized-control, double-blind, multi-center, delayed-start, pilot trial evaluating the disease modifying effects of a 150mg once-a-day dose vs. placebo of dabigatran in men and women, between the ages of 50-85 years, confirmed with MCI probably due to AD and mild Alzheimer's Disease.

Description:

The study will be conducted in 2-phases. The Phase I double-blind portion of the study consists of 40-60 active participants with MCI probably due to AD and mild AD randomized to 150mg once-a-day dose of dabigatran or placebo. A futility analysis will be conducted based on month 3 plasma biomarker changes from baseline. Excluding futility, at the end of Phase I, the study continues onto the open-label phase of the study where the placebo arm will be treated with 150mg once-a-day with dabigatran from months 10-21. The active treatment arm will continue on dabigatran through month-21. For final analysis, a difference in intercept of a generalized growth model between randomization groups during Phase 2 in the Cognitive Dementia Rating Scale-Sum of Boxes (CDR-SB) will be taken as evidence of effectiveness and justify further study. All patients will discontinue dabigatran after month 21 and a 3-month follow-up period will confirm whether or not the proposed cognitive effects can be sustained in the absence of treatment. The relationships between changes in levels of plasma biomarkers over time will be tested with regards to each other and relative to MRI and cognitive testing performed at scheduled intervals.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: December 2021
• Est. primary completion date: November 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 85 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of MCI likely due to AD or mild AD based on IWG-2 criteria for typical AD (A plus B at any stage) 2011 revised criteria

2. English speaking men & woman age 50 -85 years (inclusive)

3. Ability to provide informed consent

4. MMSE score >20 at screening

5. Informant or caregiver (e.g. family member, friend) willing to participate in semi-structured interviews

6. CSF Aß positive (MCI and AD) or a positive amyloid positron emission tomography (PET) scan within 6-months prior to screening using IWG-2 criteria.

7. CDR Scale Global Score between 0.5 and 1

8. Stable dosing (prior 3-months) of standard AD medications are allowed

9. Demonstrated willingness to comply with study visit schedule, laboratory studies, and other study procedures

Exclusion Criteria:

1. Pre-menopausal women (last menstruation < 1 year prior to screening) who are not surgically sterile.

2. Creatinine clearance < 50mL/min

3. Current psychiatric or neurological disorder that would contribute to cognitive impairment (focal neurological features early extrapyramidal signs, early hallucinations, cognitive fluctuations, non-AD dementia, major depression)

4. Cerebrovascular disease

5. Toxic, inflammatory, and metabolic disorders, all of which may require specific investigations

6. MRI Flair or T2 signal changes in the medial temporal lobe that are consistent with infectious or vascular insults

7. Sudden onset or early occurrence of the following symptoms: gait disturbances, seizures, major and prevalent behavioral changes

8. Inability to swallow pills

9. Current anticoagulant therapy

10. Conditions associated with an increased risk of bleeding (e.g. major surgery within 30-days of baseline, planned surgery or intervention during treatment period)

11. History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding

12. Gastrointestinal hemorrhage within the past year

13. Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30-days; hemorrhagic disorder or bleeding diathesis

14. Need for anticoagulant treatment of disorders, fibrinolytic agents within 48-hours of study baseline, uncontrolled hypertension (systolic blood pressure greater than 180mm Hg and/or diastolic blood pressure greater than 100 mm Hg)

15. Recent malignancy or radiation therapy (within 6-months) and a survival rate of 3-years,

16. Active infective endocarditis

17. Active liver disease (including but not limited to persistent ALT, AST, Alk Phos greater than twice the upper limit of the normal range; active hepatitis C (positive HCV RNA)

18. Active hepatitis B (HBs antigen +, anti HBc IgM +), active hepatitis A

19. HIV/AIDS diagnosis

MRI exclusionary criteria

1. Brain Aneurysm Clip

2. Implanted neural stimulator

3. Implanted cardiac pacemaker or defibrillator

4. Cochlear implant

5. Ocular foreign body (e.g. metal shavings)

6. Other implanted medical devices: (e.g. Swan Ganz catheter, mechanical prosthetic heart)

7. Insulin pump

8. Metal shrapnel or bullet

Additional concomitant drug exclusionary criteria will be applied by investigator.

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Mild Alzheimer's Disease
• Mild Cognitive Impairment

Intervention

Drug:
• Dabigatran
At the end of a 9-month randomized-control, double-blind treatment all study participants will cross-over to the 12-month open-label phase with a 3-month non-treatment follow-up.
• Placebo - Cap
At the end of a 9-month randomized-control, double-blind treatment all study participants will cross-over to the 12-month open-label phase with a 3-month non-treatment follow-up

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
University of Rhode Island	Alzheimer’s Drug Discovery Foundation, Boehringer Ingelheim

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluate dabigatran efficacy in MCI and mild AD population using changes in targeted plasma and CSF biomarker levels at 9 and 21 months	Evaluate effectiveness of dabigatran (150mg daily) on disease modification measured by changes in targeted plasma and CSF biomarkers associated with the early stages of Alzheimer's disease	9 and 21-months
Secondary	Demonstrate a reduction in decline of cognitive function related to physical functioning in placebo arm after crossing over to 12-months of active treatment	Demonstrate an observed benefit of cognitive performance/function using the ADCS ADL MCI	12 - 24 months
Secondary	Changes in cognitive performance in placebo arm after cross-over to open-label treatment phase	Evaluate effectiveness of dabigatran (150mg daily) using the CDR-SB	24-months
Secondary	Safety and tolerability of dabigatran in experimental population (MCI and mild AD populations) based on reported serious and adverse events	Determine the safety and tolerability of dabigatran in MCI probably due to AD and mild AD population using physician and patient reported adverse events.	21-months
Secondary	Evaluation of cognitive performance in placebo arm after cross-over to open-label treatment phase	Evaluate effectiveness of dabigatran (150mg daily) using the MoCA	24-months