MK-8931 (EPOCH)

Overview

Status: Not yet recruiting
Keywords: Mild to Moderate Alzheimer's disease , dementia , Merck 8931-017-03 , Oral Medication , MK-8931 (EPOCH)
IRB Number: 00065220
Specialty: Neurology
Sub Specialties: Alzheimer's Disease

Brief Summary

Part I Primary Trial Objectives:

1.       To assess the efficacy of two doses of MK-8931 on cognition in subjects with mild to moderate AD.

2.       To assess the efficacy of two doses of MK-8931 on functional ability in activities of daily living in subjects with mild to moderate AD.

3.       To assess the safety and tolerability of three doses of MK-8931 in the treatment of subjects with mild to moderate AD.

Part I Secondary Trial Objective: To assess the overall clinical response, as reflected by global assessment, of two doses of MK-8931 in subjects with mild to moderate AD.

PART I Other Secondary Trial Objectives and Hypotheses:  To assess the effect of two doses of MK-8931 on cortical amyloid load assessed using [18F]Flutemetamol and PET imaging in subjects with mild to moderate AD included in the PET substudy. 

Part II: Primary Extension Objectives:

1.     To evaluate the safety and tolerability of MK-8931 in the long term treatment of mild to moderate AD.

2.    To compare the efficacy of MK-8931 on cognition and functional ability in activities of daily living in subjects with mild to moderate AD administered MK-8931 for 24 months to that of subjects administered placebo for 18 months followed by MK-8931 for 6 months.

Part II: Exploratory Extension Trial Objective:

To compare the efficacy of MK-8931 administered to subjects for 18 months to that of subjects administered placebo for 18 months in Part I followed by long term treatment of MK-8931 in Part II on cognition, function, disease progression, and health economic burden at multiple time points.

Principal Investigator: Edward Zamrini
Department: Alzheimer's Center
Co Investigator: Norman Foster
Co Investigator: Richard King

Contact Information

Name:Joshua Amaro
Phone: 581-3986
Email: josh.amaro@hsc.utah.edu

Inclusion Criteria

Protocol Amendment 4 update:  Enrollment for the Safety Cohort has closed.  Our site will recruit only for the Main Cohort.  We plan to enroll 10 participants and may enroll up to 12 participants with Sponsor approval.  Some inclusion/exclusion criteria have been revised.  Changes are noted within the numbered inclusion/exclusion lists below.

At our site we expect to consent and screen up to 20 participants for the Main Cohort.  We expect up to 10 participants to meet inclusion criteria for the Main Cohort and be randomized to study drug.

Subjects must meet all the criteria listed below to participate in the trial.

Protocol A5 change:  The study has been divided into two parts:  Part I - Main Trial, Part II - Extension Trial.

Part I Inclusion Criteria:

1.       Be ≥ 55 to ≤ 85 years of age at the first visit.

2.       Meet the criteria for a diagnosis of probable AD based on both:

a.       National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria,  and

b.      Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD.

3.       Have an MMSE score ≥ 15 and ≤ 26 at Screening

4.       Have a clear history of cognitive and functional decline over at least one year that is either a) documented in medical records or b) documented by history from an informant who knows the subject well.

5.       Have an MRI scan at the Screening Visit that is consistent with a diagnosis of AD.

6.       Be able to read at a 6th grade level or equivalent, as determined by the investigator, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation.

7.       If a subject is receiving an acetylcholinesterase inhibitor, memantine and/or herbal medications for AD, the dose must have been stable for at least three months before Screening, and the subject must be willing to remain on the same dose for the duration of the trial. (The treatment and dose at Screening must not be changed during the trial unless medically necessary. Additional treatments [including herbal medications] for AD that are not specified in the protocol must not be initiated during the trial.) The subject and caregiver must agree that they do not plan to discontinue treatment or initiate additional AD treatments during the trial unless medically necessary.  

Protocol A4 change:  If a subject is receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement, and/or herbal medications for AD, the dose must have been stable for at least 3 months before screening, and the subject must be willing to remain on the same dose for the duration of the trial.  Subjects may need to be on AD treatments in accordance with local requirements.

8.       Subjects in the Main cohort must have a reliable and competent trial partner/caregiver who has a close relationship with the subject, has face to face contact at least three days a week for a minimum of six waking hours a week, is willing to accompany the subject to all trial visits, and is willing to monitor compliance of the administration of the trial medication. The trial partner/caregiver should understand the nature of the trial and adhere to trial requirements (eg, dose, visit schedules, and evaluations).  Subjects in the safety cohort must have face to face contact at least five days a week for a minimum of 10 waking hours a week.

Protocol A4 change:  Each subject must have a reliable and competent trial partner/caregiver who must have a close relationship with the subject, have face to face contact at least three days a week for a minimum of six waking hours a week, (or more in accordance with local requirements), be willing to accompany the subject to all trial visits, and be willing to monitor compliance of the administration of the trial medication.

9.       Have results of clinical laboratory tests (complete blood count [CBC], blood chemistries, thyroid stimulating hormone [TSH], and urinalysis) within normal limits or clinically acceptable to the investigator at Screening.

10.   Have results of a physical examination, vital signs, and ECG within normal limits or clinically acceptable to the investigator at Screening.

11.   Female subjects must have:

a.       reached natural menopause (defined as  46 years of age with either ≥ 12 months of spontaneous amenorrhea or  ≥ 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels  40 IU/L as determined by the central laboratory); Pregnancy is to be ruled out by a negative serum βhCG before the first administration of trial medication.

b.      had a hysterectomy;

c.       had a bilateral tubal ligation; or

d.      had a bilateral oophorectomy (with or without a hysterectomy) and greater than 6 weeks have passed since the surgery.

12.   Be willing to provide a blood sample for APOE genotyping.

Protocol A4 change: Each subject must be willing to provide a blood sample for APOE and HLA genotyping.

13.   Based on the investigator's judgment, be able to speak, read, hear, and understand the language of the trial staff and the informed consent form, and possess the ability to respond verbally to questions, follow instructions, and complete questionnaires. Each subject must also be able and willing to adhere to dose and visit schedules and to consent to video/audio recording of selected interviews.

14.   Sign the informed consent form after the scope and nature of the investigation have been explained to them, and before screening assessments.  If appropriate, the subject’s legal representative may provide written consent on behalf of the subject.

Subjects who agree to participate in pharmacogenetic testing must give written informed consent for pharmacogenetic testing. Subjects who are unwilling to sign the informed consent for pharmacogenetic testing may be included into the trial, however, pharmacogenetic samples must not be obtained.

Protocol A4 change:  Each subject (or legal representative) must sign the informed consent form in accordance with local requirements, after the scope and nature of the investigation have been explained to them, and before Screening assessments.

Part II Inclusion Criteria (Protocol A5 change)

Each subject must have tolerated study medication and completed the initial 78-week period of the trial.  Subjects who did not complete the initial 78 weeks of treatment may be permitted to continue in the extension at the discretion of the Sponsor.

Each subject must have a trial partner who is reliable and competent.  The trial partner must have a close relationship with the subject, have face to face contact at least 3 days/wk for a minimum of 6 waking hours/wk (or more, based on local requirements), be willing to accompany the subject to all trial visits, and be willing to monitor compliance of the administration of the trial medication.  The trial partner should understand the nature of the trial and adhere to trial requirements (e.g. dose, visit schedules, and evaluations).  It is recommended that the trial partner accompany the subject to all trial visits.

Exclusion Criteria

Part I Exclusion Criteria:

A subject meeting any of the exclusion criteria listed below must be excluded from the trial:

1.       Rosen-modified Hachinski Ischemia Score > 4 at Screening (i.e., evidence of vascular dementia).

2.       Known history of stroke or evidence from screening MRI scan that is clinically important in the investigator's opinion.

3.       Evidence of a clinically relevant neurological disorder other than probable AD at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or head trauma with loss of consciousness that led to persistent cognitive deficits.

Protocol A4 Changes:  The subject has evidence of a clinically relevant neurological disorder other than the disease being studied (ie, probable AD) at Screening, including but not limited to: vascular dementia, parkinsonism, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, neurosyphilis, dementia with Lewy bodies, posterior cortical atrophy, logopenic primary progressive aphasia, other types of dementia, mental retardation, hypoxic cerebral damage, cognitive impairment due to other disorders, or head trauma with loss of consciousness that led to persistent cognitive deficits.

4.       History of seizures or epilepsy within the last 5 years before Screening.

5.       Evidence of a clinically relevant or unstable psychiatric disorder, based on DSM-IV-TR criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium. Major depression in remission is not exclusionary.

6.       Evidence of a current episode of major depression based on investigator's judgment. A score on the 15-item Geriatric Depression Scale of 5 or more requires an assessment by an appropriate health care professional to evaluate for the presence of major depression. Subjects with a score of 5 or more who are not diagnosed with major depression following such an assessment may be included in the trial.

7.       At imminent risk of self-harm, based on clinical interview or on the Columbia Suicidality Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan (i.e., suicidal ideation Type 4 or 5 on the C-SSRS) in the past 1 month or suicidal behavior in the past 6 months.

8.       History of alcoholism or drug dependency/abuse within the last 5 years before Screening.

9.       Unwilling or not eligible to undergo an MRI scan (eg, metal implants, obesity).

10.   MRI scan obtained at Screening shows evidence of:

a.        a neurological disorder other than probable AD or

b.      > 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"),

c.       a single area of superficial siderosis,

d.      evidence of a prior macrohemorrhage,

e.      > 3 lacunar infarcts,

f.        any cortical infarct over 10 mm,

g.       or any other clinically significant finding (eg, any lesion that may account for their cognitive impairment, including but not limited to brain tumor, severe white matter disease, arteriovenous malformation, cavernous hemangioma, or any infarct in a strategic subcortical location).

11.   At Screening has

a.       alanine aminotransferase (ALT) ≥ 3 x upper limit of normal (ULN), OR

b.      aspartate aminotransferase (AST) ≥ 3 x ULN, OR

c.       total bilirubin (T-BIL) ≥ 1.5 x ULN.

       i.      Should a liver function test (LFT) be abnormal (ALT/AST >ULN but < 3x ULN, T-BIL > ULN but < 1.5 x ULN) at Screening but not meet the specified criteria, the investigator should attempt to characterize at entry the reason(s) for the elevation (eg, alcohol abuse, metabolic syndrome with fatty liver, etc.).

       ii.      Subjects with suspected Gilbert's Syndrome who have isolated T-BILI ≥ 1.5 x ULN may enter the trial upon genetic confirmation (eg, uridine diphosphate glucuronosyltransferase 1A1 [UGT1A1] assessment).

12.   History of hepatitis or liver disease that, in the opinion of the investigator, has been active within the six months prior to Screening.

13.   Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit other than the condition being studied such that, in the judgment of the investigator, participation in the trial would pose a significant medical risk to the subject.   (Such as, but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function with estimated creatinine clearance < 30 mL/min.)

Controlled co-morbid conditions (including diabetes, hypertension, heart disease, etc.) are not exclusionary if stable within three months of the Screening Visit. All concomitant medications, supplements (e.g. Vitamin E), or other substances must be kept as stable as medically possible during the trial.  Note: urinary tract infections at screening are not exclusionary if adequately treated (as documented by repeat urinalysis) prior to baseline.

14.   History or current evidence of long QT syndrome, QTC interval ≥ 470 milliseconds (for male subjects) or ≥ 480 milliseconds (for female subjects), or torsades de pointes.

Protocol A4 Changes:  The subject has a history or current evidence of long QT syndrome, QTC interval ≥ 470 milliseconds (for male subjects) or ≥ 480 milliseconds (for female subjects), or torsades de pointes. (Note: Determination of QTc interval at Screening will be based on the average of three measurements, using the Fridericia formula for correction.)

15.   History of malignancy occurring within the five years immediately before Screening, except for a subject who has been adequately treated for:

a.        basal cell or squamous cell skin cancer,

b.       in situ cervical cancer, or

c.        localized prostate carcinoma; or

d.      has undergone potentially curative therapy with no evidence of recurrence for ≥ 3 year post-therapy, and who is deemed at low risk for recurrence by her/his treating physician.

16.   Has clinically significant vitamin B12 or folate deficiency in the six months immediately before screening or vitamin B12 or folate deficiency in addition to increased serum homocysteine or methylmelonic acid levels at screening as determined by central laboratory normal values.

17.   Is pregnant, attempting to become pregnant, or nursing children.

18.   Received any protocol-prohibited medications, supplements or other substances more recently than the indicated period before screening.

19.   Anticipates receiving any of the protocol-prohibited medications, supplements or other substances during the current trial.

Please see the document "Prohibited Medications, Supplements and Other Substances" in the "Other Documents" page of this study application for a complete list of prohibited medications.  

20.  Known allergy or sensitivity to the excipients in the investigational product(s).

21.  Any clinically significant condition or situation, other than the condition being studied, that, in the opinion of the investigator, would interfere with the trial evaluations, required procedures (eg, ophthalmological monitoring) or optimal participation in the trial.

22.  Has used any investigational drugs or has been participating in any other clinical trial within the 30 days immediately before Screening.

23.  History of a hypersensitivity reaction to more than three drugs.

24.  History of erythroderma (exfoliative dermatitis), DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), Stevens-Johnson Syndrome or toxic epidermal necrolysis.

25.  Has tested positive for HIV.

26.  Has a close family member (including the caregiver) who is among the personnel of the investigational or sponsor staff directly involved with this trial.

27.  Has exudative (wet) age-related macular degeneration, active proliferative diabetic retinopathy, myopia or hyperopia > 8 diopters, pigment dispersion syndrome, pseudo-exfoliation syndrome, pigmentary glaucoma, glaucoma that requires > 2 classes of medications, IOP > 21 mmHg (at the Screening Visit), clinically significant macula edema with diabetic retinopathy or advanced cataract to the degree that does not allow SD-OCT measurement, nystagmus, or other significant retinal diseases causing such significant distortion that baseline measurements would be too greatly abnormal to allow reasonable detection of possible change.

Additional Exclusion Criteria for Safety Cohort - Our site is not participating in the Safety Cohort

Additional Exclusion Criteria for the CSF Substudy

31.  Increased intracranial pressure (ICP), bleeding diathesis (eg, from use of anticoagulants), skin infection at lumbar puncture (LP) site, or prior history of LP-associated headache(s).

Additional Exclusion Criteria for PET Sub-Study (added with 2014 Renewal)

32. The subject has been exposed to ionizing radiation > 15mSv in other research studies within the last 12 months.  Radiation exposure from routine medical procedures or other non-research activities is not considered part of the criteria for the 15 mSv limit.

33.  The subject has had any surgical or medical condition which might significantly alter the distribution, metabolism, or excretion of [18 F] Flutemetamol.

34.  The subject has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth.

35.  The subject has a BMI under 18 or over 35 at the Screening Visit.

 

Part II Exclusion Criteria (Protocol A5 Update):

The subject is at imminent risk of self-harm, based on clinical interview or C-SSRS, or of harm to others in the opinion of the investigator.  Subjects must be excluded if they report suicidal ideation with intent, with or without a plan in the past 1 month or suicidal behavior in the past 6 months.

The subject has developed a recent or ongoing, uncontrolled, clinically significant medical condition (such as, but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis or abnormal renal function with estimated creatinine clearance < 30 mL/min) other than AD such that, in the judgement of the investigator, participation in the trial would pose a significant medical risk to the subject.  Controlled co-morbid conditions are not exclusionary if stable.  All concomitant medications, supplements (e.g. Vitamin E), or other substances must be kept as stable as medically possible during the trial.

Note:  Urinary tract infections at screening are not exclusionary if adequately treated (as documented by repeat urinalysis).

The subject has a history of or has developed during Part I, evidence of long QT syndrome, QTC interval >470 milliseconds (for male subjects or > 480 milliseconds (for female subjects), or torsades de pointes.

The subject anticipates receiving any of the treatments listed in Table 13 during Part II.

The subject has developed a form of dementia that is not AD, as determined by the investigator.