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Safety and Modulation of ABCC9 Pathways by Nicorandil for the Treatment of Hippocampal Sclerosis of Aging (SMArT-HS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04120766
Recruitment Status : Not yet recruiting
First Posted : October 9, 2019
Last Update Posted : October 23, 2020
Sponsor:
Information provided by (Responsible Party):
Gregory Jicha, MD, PhD, University of Kentucky

Brief Summary:
Widespread recognition of the current and projected impact of the dementia epidemic has spurred research into novel drug discovery efforts. It is well recognized by most that Alzheimer's disease is not the only form of dementia and that beginning to turn attention to other disease states is critically important in order to alleviate this burden on the elderly population today This proposal seeks to further progress in this area through the repurposing an existing drug therapy as a potential treatment for Hippocampal Sclerosis of Aging. This disease is seldom recognized clinically and yet is the number one Alzheimer's disease mimic the confounds are diagnostic and treatment of subjects suffering from dementia and as of yet has no potential therapeutic interventions identified. As such, the proposed study represents a cutting-edge, data-driven, low-cost, exploration of a novel disease relevant pathway that may hold promise for global efforts targeting late life dementia which is a major health priority in America today.

Condition or disease Intervention/treatment Phase
Dementia Mild Cognitive Impairment Drug: Nicorandil Drug: Placebo Phase 2

Detailed Description:
The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging), a prevalent, high-morbidity mimic of Alzheimer's disease (AD). "AD mimics" (diseases with pathologies other than AD but with similar symptoms) are increasingly appreciated to be important causes of dementia. HS-Aging is a major subtype of dementia, affecting ~10-25% of all persons beyond age 85 and is generally misdiagnosed as AD. The primary aims of this study are to test the safety and efficacy of nicorandil for HS-Aging, based on much prior work elucidating a pharmacologically targetable mechanism for this common cause of cognitive decline and dementia in the aging population. Nicorandil is a vasorelaxant drug, used clinically to treat angina and heart disease disease in the elderly, that has not been tested in humans for the prevention or treatment of dementia. The proposed pilot clinical trial represents the first attempt to expedite drug discovery in HS-Aging, and will guide the rational design of future large-scale Phase II & III prevention trials for this prevalent disease that is a major contributor to the personal suffering of patients and caregivers as well as a major cost to health care expenditures in America today. The potential success of this trial will not only help millions within immediately available treatment for their condition but may also ameliorate the booming economic burden of healthcare costs in America today related to late life dementia.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Double-blind, placebo controlled, randomized 1:1, single center study of nicorandil (20 mg by mouth daily) or placebo for 96 weeks.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind, placebo controlled, randomized 1:1, single center study of nicorandil (20 mg by mouth daily) or placebo for 96 weeks.
Primary Purpose: Treatment
Official Title: Safety and Modulation of ABCC9 Pathways by Nicorandil for the Treatment of Hippocampal Sclerosis of Aging: SMArT-HS
Estimated Study Start Date : November 1, 2020
Estimated Primary Completion Date : November 1, 2024
Estimated Study Completion Date : November 20, 2024

Arm Intervention/treatment
Experimental: Treatment
Nicorandil 20mg qd
Drug: Nicorandil
20 mg po qd

Placebo Comparator: Placebo
Matched placebo qd
Drug: Placebo
Matching tablet




Primary Outcome Measures :
  1. Frequency of subjects by arm that experience treatment-related adverse events at week 96 [ Time Frame: 96 weeks ]
    Safety


Secondary Outcome Measures :
  1. Hippocampal volume (CC) [ Time Frame: 96 weeks ]
    Change in hippocampal volume over time using freesurfer analyses



Information from the National Library of Medicine

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Ages Eligible for Study:   75 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Men or women at least age 75 years
  2. UPDRS ≤ 7
  3. Hachinski Ischemic Score ≤ 4
  4. CSF profile of "A-T-N+" defined as Aβ(1-42)>250pg/ml; Total Tau>50pg/ml; Phospho-tau<30pg/ml; hippocampal volume ≤ 1 s.d. below age and gender adjusted mean
  5. English-speaking, to ensure compliance with cognitive testing and study visit procedures
  6. Involvement of a study partner to supervise medications and compliance with study visits/procedure
  7. Stable medical conditions for three months prior to screening visit, with no clinically significant abnormalities of hepatic, renal, and hematologic function defined in the opinion of the investigator
  8. Stable medications for 4 weeks prior to screening visit
  9. Ability to ingest oral medications
  10. Physically acceptable for this study as confirmed by medical history, physical exam, neurological exam and clinical tests.

Exclusion Criteria:

  1. Significant neurologic disease such as Parkinson's disease, stroke, brain tumor, multiple sclerosis or seizure disorder
  2. Major depression in past 12 months (DSM-IV criteria)
  3. Recent (in past 12 months) substance abuse
  4. History of cancer within the past two years, with the exception of non-metastatic prostate or non-melanoma skin cancers such as squamous cell and basal cell carcinomas
  5. Contra-indications to lumbar puncture (bleeding disorder, platelet count < 100,000, anticoagulant treatment, major abnormality of the spine that would make LP technically difficult)
  6. Use of any investigational agents within 30 days prior to screening
  7. Major surgery within eight weeks prior to the Baseline Visit
  8. Severe unstable medical illnesses, including uncontrolled cardiac conditions or heart failure (New York Heart Association Class III or IV)
  9. Blindness, deafness, or any other disability which may prevent the participant from participating or cooperating in the protocol.

Excluded Medications*

Participants are not eligible for participation in the study if they are taking:

  1. Experimental drugs
  2. Vasoactive nitrates such as isosorbide dinitrate
  3. Drugs for erectile dysfunction such as sildenafil, vardenafil, and tadalafil among others
  4. Sulfonylurea antidiabetic agents that may confound efficacy measures for the secondary efficacy outcome measures.

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): NCT04120766


Contacts
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Contact: Gregory A Jicha, MD, PhD 18593235550 gregory.jicha@uky.edu

Sponsors and Collaborators
Gregory Jicha, MD, PhD
Investigators
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Principal Investigator: Gregory A Jicha, MD, PhD University of Kentucky
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Responsible Party: Gregory Jicha, MD, PhD, MD-PhD Professor of Neurology, University of Kentucky
ClinicalTrials.gov Identifier: NCT04120766    
Other Study ID Numbers: NIA 1R01AG061111
First Posted: October 9, 2019    Key Record Dates
Last Update Posted: October 23, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified data will be shared to other researchers upon request and approval by the study leaders to ensure that data requests do not impinge on the reporting of the primary outcomes or influence study conduct or post conduct analyses. Such IPD will be made available one year following publication of the primary manuscript
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: one year following publishing the primary study results

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gregory Jicha, MD, PhD, University of Kentucky:
TDP-43
Hippocampal sclerosis
Additional relevant MeSH terms:
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Sclerosis
Cognitive Dysfunction
Pathologic Processes
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Nicorandil
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs