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Trial record 3 of 124 for:    prodromal

Dose-Finding Study To Evaluate the Safety and Tolerability of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT02322021
Recruitment Status : Active, not recruiting
First Posted : December 22, 2014
Last Update Posted : October 18, 2017
Sponsor:
Collaborator:
Biogen
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:
This is a Phase 2 study to evaluate safety and tolerability of daily dosing with elenbecestat (proposed international proprietary name [pINN]) (E2609) in Mild Cognitive Impairment (MCI)/Prodromal participants and in participants with Mild to Moderate Dementia due to Alzheimer's Disease (referred to as mild to moderate AD).

Condition or disease Intervention/treatment Phase
Alzheimer Disease Dementia, Alzheimer Type Drug: elenbecestat (E2609) Drug: Placebo Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 71 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Dose-Finding Study To Evaluate the Safety and Tolerability of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease
Actual Study Start Date : November 2014
Estimated Primary Completion Date : March 2018
Estimated Study Completion Date : April 2018


Arm Intervention/treatment
Experimental: MCI/Prodromal Cohort: Low Dose
A low dose of elenbecestat (E2609) will be assessed. After 6 or more months of treatment with a low dose of elenbecestat (E609), participants with at least 3 months of treatment remaining will be re-assigned to receive a high dose of elenbecestat (E2609) for the remainder of the double-blind treatment period. Eligible participants will receive a high dose of open-label elenbecestat (E2609) during the Open-Label Extension (OLE) Phase.
Drug: elenbecestat (E2609)
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally once per day (QD) with food. During the OLE Phase, participants will receive a single tablet of elenbecestat (E2609).
Experimental: MCI/Prodromal Cohort: Middle Dose
A middle dose of elenbecestat (E2609) will be assessed. After 6 or more months of treatment with a middle dose of elenbecestat (E2609), participants with at least 3 months of treatment remaining will be re-assigned to receive a high dose of elenbecestat (E2609) for the remainder of the double-blind treatment period. Eligible participants will receive a high dose of open-label elenbecestat (E2609) during the OLE Phase.
Drug: elenbecestat (E2609)
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally once per day (QD) with food. During the OLE Phase, participants will receive a single tablet of elenbecestat (E2609).
Experimental: MCI/Prodromal Cohort: High Dose
A high dose of elenbecestat will be assessed during the double-blind treatment period and during the OLE Phase for participants meeting OLE eligibility criteria.
Drug: elenbecestat (E2609)
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally once per day (QD) with food. During the OLE Phase, participants will receive a single tablet of elenbecestat (E2609).
Placebo Comparator: MCI/Prodromal Cohort: Placebo
During the double-blind portion of the study, two matching placebo tablets will be administered daily. During the OLE Phase, participants will receive the high dose as a single tablet.
Drug: Placebo
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally QD with food.
Experimental: Mild to Moderate AD Cohort: Low Dose
A low dose of elenbecestat (E2609) will be assessed. After 6 or more months of treatment with a low dose of elenbecestat (E2609), participants with at least 3 months of treatment remaining will be re-assigned to receive a high dose of elenbecestat (E2609) for the remainder of the double-blind treatment period. Eligible participants will receive a high dose of open-label elenbecestat (E2609) during the OLE Phase.
Drug: elenbecestat (E2609)
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally once per day (QD) with food. During the OLE Phase, participants will receive a single tablet of elenbecestat (E2609).
Experimental: Mild to Moderate AD cohort: Middle Dose
A middle dose of elenbecestat (E2609) will be assessed. After 6 or more months of treatment with a middle dose of elenbecestat (E2609), participants with at least 3 months of treatment remaining will be re-assigned to receive a high dose of elenbecestat (E2609) for the remainder of the double-blind treatment period. Eligible participants will receive a high dose of open-label elenbecestat (E2609) during the OLE Phase.
Drug: elenbecestat (E2609)
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally once per day (QD) with food. During the OLE Phase, participants will receive a single tablet of elenbecestat (E2609).
Experimental: Mild to Moderate AD Cohort: High Dose
A high dose of elenbecestat will be assessed during the double-blind treatment period and during the OLE Phase for participants meeting OLE eligibility criteria.
Drug: elenbecestat (E2609)
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally once per day (QD) with food. During the OLE Phase, participants will receive a single tablet of elenbecestat (E2609).
Placebo Comparator: Mild to Moderate AD Cohort: Placebo
During the double-blind portion of the study, two matching placebo tablets will be administered daily. During the OLE Phase, participants will receive the high dose as a single tablet.
Drug: Placebo
In the double-blind portion of the study, each participant will receive two tablets, which when combined will make up the required dose of elenbecestat (E2609) or placebo, to be administered orally QD with food.



Primary Outcome Measures :
  1. Number of treatment emergent adverse event (TEAEs) and serious adverse events (SAEs) [ Time Frame: From the time the participant signs the informed consent form until up to 3 months after the last dose of study drug or up to approximately 51 months ]

Secondary Outcome Measures :
  1. Percentage change from baseline in cerebrospinal fluid (CSF) Abeta(1-x) and Abeta(1-42) after 4 weeks and 18 months of treatment in MCI/Prodromal participants and mild to moderate AD participants [ Time Frame: At 4 weeks and 18 months of treatment ]
  2. Mean plasma concentration of elenbecestat, including the effect of intrinsic and extrinsic factors [including N-acetyltransferase 2 (NAT2) phenotype] [ Time Frame: Baseline; predose (trough) and 1 to 6 hours postdose at Week 3, Week 13, Week 27, and Week 53; and 4 to 8 hours postdose at Week 5 and Week 79 (or early discontinuation) ]
  3. Mean CSF concentration of elenbecestat, including the effect of intrinsic and extrinsic factors [including N-acetyltransferase 2 (NAT2) phenotype] [ Time Frame: Baseline, Week 5, Week 79 (or early discontinuation) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Participants must meet all of the following criteria to be included in the Core Study (Prerandomization and Randomization Phases):

  1. Meets the core clinical research criteria of the NIA-AA for MCI due to AD (which is consistent with Prodromal AD) or AD dementia and is 'staged' or classified as either MCI or mild to moderate dementia.
  2. Amyloid positive Positron Emission Tomography (PET) image based on centralized PET scan reading.
  3. Male or female, age 50 to 85 years, inclusive at time of consent.
  4. Must have an identified caregiver or informant who is willing and able to provide follow-up information on the participant throughout the course of the study.
  5. If receiving an Acetylcholinesterase Inhibitor (AChEI) or memantine, must have been on a stable dose for at least 12 weeks before the Baseline cognitive assessments, with no plans for dose adjustment in the foreseeable future. Treatment-naive participants can be entered into the study but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry into the study.
  6. Must have been on stable doses of all other permitted chronically used concomitant medications (ie, not related to their cognitive decline) for at least 4 weeks before randomization.

Participants must meet all of the following criteria to be included in the Open-Label Extension (OLE) Phase of the study:

  1. Participants who complete the 18-month treatment and the 12-week follow-up period (Visit 20) in the Core Study and whose Visit 20 falls within a 4-week window from the start of the OLE Phase (Visit 21). Permission must be obtained from the Medical Monitor if the Visit 21 is to occur more than 4 weeks from Visit 20.
  2. Participants must continue to have an identified caregiver or informant who is willing and able to provide follow-up information on the participant throughout the course of the OLE Phase.

Exclusion criteria:

Participants who meet any of the following criteria will be excluded from the Core Study:

  1. Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's AD pathology, including any co-morbidities such as cerebrovascular disease, detected by medical history, neurological examination, or magnetic resonance imaging (MRI).
  2. History of transient ischemic attacks or stroke within 12 months of Screening.
  3. History of epilepsy.
  4. Evidence of depression on a rating scale at Screening or any psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, etc.) that could confound the diagnosis or could interfere with study assessments or procedures. This includes suicidal ideation or suicidal behavior within 6 months prior to Screening, or hospitalization or treatment for suicidal behavior in the past 5 years.
  5. Abnormally low serum vitamin B12.
  6. Thyroid stimulating hormone above the normal range. This applies to all participants regardless of whether or not they are taking thyroid supplements.
  7. Participants with liver disease (hepatic impairment), at Screening or Baseline. Participants with Gilbert's syndrome need not be excluded.
  8. Not able to have a MRI, PET scanning, or CSF collection by Lumbar Puncture (LP) (applicable to participants consenting to CSF sample collection).
  9. Severe visual or hearing impairment that would prevent the participant from performing psychometric tests accurately.
  10. History of immunodeficiency disorders.
  11. Participants with chronic viral hepatitis.
  12. History of Tuberculosis (TB). Participants with no history of TB will be tested for previous TB exposure and a positive test will be exclusionary.
  13. History of ophthalmic shingles or ocular Herpes Simplex Virus (HSV) infection.
  14. Any live vaccine in the 3 months or any active infection within the last 4 weeks before study drug administration (i.e. randomization).
  15. Any chronic inflammatory disease that is not adequately controlled or requires immunosuppressive or immunomodulatory therapy.
  16. T helper cell, cytotoxic T cell, or B cell absolute counts below normal.
  17. Immunoglobulin (Ig) IgG, IgA, or IgM levels below normal at Screening or Baseline, unless both the Investigator and the Medical Monitor agree that the finding is not clinically significant.
  18. Clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory tests at Screening or Baseline.
  19. Exclusionary cardiac factors include: prolonged QT interval greater than 450 milliseconds (msec) from electrocardiograms (ECGs); history of risk factors for torsade de pointes or the use of concomitant medications that prolong the QT/QTc interval; left bundle branch block; persistent low or high heart rate; persistent low or high blood pressure; history of cardiac arrhythmias; other clinically significant ECG abnormalities.
  20. Type 1 or Type 2 diabetes mellitus that is not well controlled.
  21. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; these do not exclude the participant).
  22. Medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably controlled, or which, in the opinion of the investigator(s), could affect the participant's safety or interfere with the study assessments.
  23. Hypopigmentation conditions (eg, albinism and vitiligo).
  24. Known or suspected history of drug or alcohol dependency or abuse within 2 years, current use of recreational drugs or a positive urine drug test.
  25. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the study.
  26. Participation in any other interventional clinical study related to cognitive impairment within 6 months before Screening unless it can be documented that the participant was in a placebo treatment arm.
  27. Currently enrolled in another clinical study or used any investigational drug or device within 60 days or 5 half-lives of the investigational medication (whichever is longer) proceeding informed consent.
  28. Hypersensitivity to the study drug or any of the excipients or to other Beta Secretase Cleaving Enzyme (BACE) inhibitors, or to the PET tracer, or components of its formulation.
  29. Females who are lactating or pregnant. Females of childbearing potential who do not agree to adhere to the protocol specified methods for avoiding pregnancy.
  30. Males who do not meet the protocol requirements for avoiding their partners becoming pregnant. Sperm donation is not permitted.

Participants who meet any of the following criteria will be excluded from the OLE Phase of the study:

  1. Participants who discontinue study drug prematurely during the Core Study are not eligible to participate in the OLE Phase.
  2. Participants with any active infection within 4 weeks of Visit 21
  3. Participants with absolute lymphocyte count below the lower limit of normal (LLN) within 10 days of Visit 21
  4. Participants who develop the following conditions from the time of screening for the Core Study to the start of the OLE Phase:

    1. Hepatic impairment, with total bilirubin greater than 1.5 × the upper limit of normal (ULN) or International Normalized Ratio (INR) greater than 1.7. Participants with Gilbert's syndrome need not be excluded on the basis of an elevated bilirubin, provided that they have no other signs or symptoms suggestive of hepatic impairment.
    2. Any contraindications to MRI scanning, including cardiac pacemaker/defibrillator or ferromagnetic metal implants (eg, in skull; cardiac devices other than those approved as safe for use in MRI scanners)
    3. Severe visual or hearing impairment that would prevent the participant from performing psychometric tests accurately
    4. Immunoglobulin (Ig) deficiency or other immunodeficiency disorders
    5. Chronic viral hepatitis
    6. Tuberculosis
    7. Ophthalmic shingles
    8. Ocular herpes simplex virus (HSV) infection
    9. Any chronic inflammatory disease that is not adequately controlled or that requires systemic or ocular immunosuppressive or immunomodulatory therapy. Participants with:

      • Seasonal or perennial allergic rhinitis, asthma or chronic obstructive pulmonary disease where the condition is considered to be stable and adequately controlled by inhaled steroids need not be excluded
      • Hashimoto's thyroiditis but who are stable on thyroid replacement therapy and not on systemic immunosuppressive therapy need not be excluded
      • Cutaneous manifestations of immunological disease that do not require systemic immunosuppressive therapy or systemic immunomodulatory therapy need not be excluded (topical steroid treatment is permitted)
    10. Malignant neoplasms (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; these do not exclude the subject from OLE).
  5. Participants with prolonged QT interval corrected by the Fridericia correction formula (QTcF) at Visit 20 or Visit 21. Participants with a single 12-lead ECG QTcF >450 msec should have 2 additional ECGs performed at least 1 minute apart and the mean QTcF from the triplicate ECGs should be calculated. Participants with a mean QTcF value >450 msec are not eligible to enter the OLE Phase.
  6. Participants with significant pathological findings on brain MRI including but not limited to: an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 centimeter at their greatest diameter need not be exclusionary).
  7. Participants who have a "yes" answer to the Columbia Suicide Severity Rating Scale (C-SSRS) suicidal ideation questions 4 or 5 at Visit 20 or Visit 21 or any suicidal behavior during the study prior to the start of the OLE Phase.
  8. Females who are lactating or pregnant. Females of childbearing potential who do not agree to adhere to the protocol specified methods for avoiding pregnancy.
  9. Participants with medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) that are not stably controlled, or which, in the opinion of the investigator(s), could affect the participant's safety or interfere with the study assessments.
  10. Any other clinically significant abnormal findings in vital signs, ECGs and laboratory tests that would, in the investigator's opinion, affect the particiapant's safety or interfere with study assessments during the OLE Phase

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): NCT02322021


  Hide Study Locations
Locations
United States, California
CITrials
Bellflower, California, United States
ATP Clinical Research
Costa Mesa, California, United States
Behavioral Research Specialists
Glendale, California, United States
Nervepro Research
Irvine, California, United States
United States, Florida
JEM Research LLC
Atlantis, Florida, United States
Elite Research and Clinical Trials LLC
Aventura, Florida, United States
Parkinson's Disease and Movement Disorders Center of Boca Raton Inc
Boca Raton, Florida, United States
Bradenton Research Center Inc
Bradenton, Florida, United States
Meridien Research
Brooksville, Florida, United States
Berma Research Group
Hialeah, Florida, United States
Galiz Research
Hialeah, Florida, United States
Alzheimers Research and Treatment Center
Lake Worth, Florida, United States
CCM Clinical Research Group
Miami, Florida, United States
Miami Jewish Health Systems
Miami, Florida, United States
Compass Research LLC
Orlando, Florida, United States
Neurostudies Inc
Port Charlotte, Florida, United States
Infinity Clinical Research
Sunrise, Florida, United States
Stedman Clinical Trials
Tampa, Florida, United States
United States, Georgia
Atlanta Center for Medical Research
Atlanta, Georgia, United States
Neurostudies Inc
Decatur, Georgia, United States
Southeastern Georgia Geriatrics
Savannah, Georgia, United States
United States, Kansas
Heartland Research Associates LLC
Wichita, Kansas, United States
United States, Michigan
Borgess Research Institute
Kalamazoo, Michigan, United States
United States, Mississippi
Precise Research Centers
Flowood, Mississippi, United States
United States, New Jersey
The NeuroCognitive Institute
Mount Arlington, New Jersey, United States
Cognitive Research Center of New Jersey
Springfield, New Jersey, United States
United States, North Carolina
ANI Neurology, PLLC dba Alzheimer's Memory Center
Charlotte, North Carolina, United States
United States, Ohio
Ohio Clinical Research Partners LLC
Canton, Ohio, United States
Neurology Diagnostics, Inc.
Dayton, Ohio, United States
United States, Pennsylvania
Abington Neurologic Associates
Willow Grove, Pennsylvania, United States
United States, Rhode Island
Rhode Island Mood and Memory Research Institute
East Providence, Rhode Island, United States
United States, South Carolina
Coastal Neurology
Port Royal, South Carolina, United States
United States, Texas
Neurology Consultants of Dallas, PA
Dallas, Texas, United States
Clinical Trials of Texas Incorporated
San Antonio, Texas, United States
Sponsors and Collaborators
Eisai Inc.
Biogen

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT02322021     History of Changes
Other Study ID Numbers: E2609-G000-202
First Posted: December 22, 2014    Key Record Dates
Last Update Posted: October 18, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Eisai Inc.:
E2609
Mild Cognitive Impairment
Mild to Moderate Dementia
Alzheimer's Disease
Prodromal Alzheimer's Disease

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Cognitive Dysfunction
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders