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Efavirenz for Patients With Mild Cognitive Impairment

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ClinicalTrials.gov Identifier: NCT03706885
Recruitment Status : Recruiting
First Posted : October 16, 2018
Last Update Posted : February 15, 2019
Sponsor:
Collaborators:
University Hospitals Cleveland Medical Center
Massachusetts General Hospital
Information provided by (Responsible Party):
Irina Pikuleva, PhD, Case Western Reserve University

Brief Summary:

This will be a two-center, placebo controlled blinded clinical trial to evaluate the safety and tolerability of efavirenz (EFV) in 36 clinically stable subjects with mild cognitive impairment/early dementia due to Alzheimer's Disease (AD) age ≥55 years. Of these 36 total subjects, 18 will be recruited by MGH and 18 will be recruited by UH. A subset of the subjects at MGH only will also participate in a Stable Isotope Labeling Kinetics (SILK) protocol with deuterated water (a nonhazardous substance), designed to more precisely measure EFV effects on CNS cholesterol turnover.

Each respective site's 18 total recruited individuals will be divided into 3 groups: these 3 groups will represent two particular dosages of EFV and a placebo group, respectively. In a double-blind fashion, participants will be receiving either a capsule of EFV or placebo daily for 20 weeks. At MGH only, 12 individuals (4 from each of the two EFV groups and placebo) will participate in the unique "heavy water" SILK protocol assessing the kinetics of deuterium enrichment in plasma 24-hydroxycholesterol (24-OHC). All study participants at both sites will have their blood, cerebral spinal fluid, and urine analyzed at various points throughout the study. All participants will have their DNA genotyped for APOE isoforms (E2, E3 or E4) and single nucleotide polymorphisms (SNPs) in CYP46A1 (rs754203) and CYP2B6 (rs3745274) to be used for post-hoc analysis.


Condition or disease Intervention/treatment Phase
Alzheimer Disease, Early Onset Drug: Sustiva Pill Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Only the Statistician and Pharmacists are unmasked
Primary Purpose: Other
Official Title: A Proof-of-Concept Clinical Research Study of Efavirenz in Patients With Alzheimer's Disease
Actual Study Start Date : December 21, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Efavirenz

Arm Intervention/treatment
Placebo Comparator: Placebo
Treatment with placebo - 1 pill per day for 20 weeks
Drug: Sustiva Pill
One pill (Sustiva 50 mg or Sustiva 200mg or Placebo) One pill per day for 20 weeks
Other Name: Efavirenz

Active Comparator: Sustiva 50mg
Treatment with Sustiva 50mg - 1 pill per day for 20 weeks
Drug: Sustiva Pill
One pill (Sustiva 50 mg or Sustiva 200mg or Placebo) One pill per day for 20 weeks
Other Name: Efavirenz

Active Comparator: Sustiva 200mg
Treatment with Sustiva 200mg - 1 pill per day for 20 weeks
Drug: Sustiva Pill
One pill (Sustiva 50 mg or Sustiva 200mg or Placebo) One pill per day for 20 weeks
Other Name: Efavirenz




Primary Outcome Measures :
  1. Serum levels of 24-hydroxycholesterol [ Time Frame: 1 year ]
    Changes in plasma 24-hydroxycholesterol (measured in ng/dL) by more or equal to 30%.


Secondary Outcome Measures :
  1. Serum levels of deuterated 24-hydroxycholesterol [ Time Frame: 1 year ]
    Serum appearance of deuterated 24-hydroxycholetserol (measured in ng/dL) will be measured within 14 days after a participant will drink the last portion of deuterated water in the Stable Isotope Kinetics Labeling Study.

  2. APOE isoform status (E2, E3, or E4) and presence of the SNPs rs754203 and rs3745274 in CYP46A1 and CYP2B6, respectively. [ Time Frame: 1 year ]
    Participants will be genotyped for the APOE isoform status (E2, E3, or E4) and presence of the SNPs rs754203 and rs3745274 in CYP46A1 and CYP2B6, respectively



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Ages Eligible for Study:   55 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Between the ages of 55-85
  • Either male or female
  • Diagnosis of (a) as per below:

    a) Mild Cognitive Impairment (MCI) or early dementia due to AD as defined by (1) complaint of cognitive decline, (2) MMSE Total=20-30, (3) CDR=0.5-1

  • Fluent in English
  • Education >8 years, literate, and/or good working history that precludes consideration of mental retardation
  • Visual and auditory acuity sufficient for neuropsychological testing
  • Modified Hachinski Ischemic Score<4
  • No major health issues or diseases expected to interfere with the study
  • Willing to complete all assessments and study procedures
  • Not pregnant, lactating or of child-bearing potential (women must be >2 years post- menopausal or surgically sterile)
  • If cognitively impaired, study partner with frequent contact with patient willing to accompany patient to visits and complete partner study forms
  • No contraindication or hypersensitivity to EFV
  • Screening laboratory testing must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigators
  • Stable use of cholinesterase inhibitor is permitted if doses are stable for 3 months prior to enrollment

Exclusion Criteria:

  • Any CNS disease other than suspected prodromal or early AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, brain tumor, multiple sclerosis, significant head trauma with persistent neurological or cognitive deficits or complaints, Parkinson's Disease, frontotemporal dementia, or other neurodegenerative diseases
  • Major psychiatric illness (e.g., depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year
  • Current suicidal ideation or history of suicide attempt
  • History of alcohol or other substance abuse or dependence within the past two years
  • Any significant systemic illness or unstable medical condition that could affect study compliance, including a history of prolonged QTc
  • Laboratory abnormalities in B12, TSH, or other common laboratory parameters that might contribute to cognitive dysfunction
  • Current use of medications with psychoactive properties that may deleteriously affect cognition (e.g., anticholinergics, antihistamines, antipsychotics, sedative hypnotics, anxiolytics)
  • Use of other investigational agents one month prior to entry and for the duration of the study
  • Treatment with any of the following agents/classes within the past 3 months: HMG-COA reductase inhibitors (i.e., statins), antiepileptic agents, rifampin, buproprion, sertraline, citalopram, zolpidem, aripiprazole, clopidogrel, capofungin, voriconazole, systemic ketoconazole, cyclosporine, St. John's Wort

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): NCT03706885


Locations
United States, Ohio
Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Irina Pikuleva, PhD    216-368-3823    iap8@case.edu   
Contact: Sangeetha Raghupathy, BS (Optom)    216-844-8552    sxr410@case.edu   
Principal Investigator: Alan Lerner, MD         
Principal Investigator: Steven Arnold, MD         
Sponsors and Collaborators
Case Western Reserve University
University Hospitals Cleveland Medical Center
Massachusetts General Hospital

Publications:

Responsible Party: Irina Pikuleva, PhD, Professor, Case Western Reserve University
ClinicalTrials.gov Identifier: NCT03706885     History of Changes
Other Study ID Numbers: ADDF 20160601
First Posted: October 16, 2018    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Efavirenz
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers