MK 7622 or Merck Connect

Overview

Status: Recruiting
Keywords: Alzheimer's Disease , Donepezil
IRB Number: 00067990
Specialty: Neurology
Sub Specialties: Alzheimer's Disease

Brief Summary

Primary Objectives:

  1. To evaluate the efficacy of MK-7622 as adjunct therapy to donepezil in improving cognition as assessed by Alzheimer’s Disease Assessment Scale-Cognitive Subscale11 in subjects with mild to moderate AD at 12 weeks.
  2. To assess the safety and tolerability of MK-7622 for up to 24 weeks of treatment.

Secondary Objectives:

1.       To evaluate the efficacy of MK-7622 as adjunct therapy to donepezil in improving function as assessed by Alzheimer’s Disease Cooperative Study-Activities of Daily Living in subjects with mild to moderate AD at 24 weeks.

2.       To evaluate the efficacy of MK-7622 as adjunct therapy to donepezil in improving cognition as assessed by the Composite Cognition Score-3 Domain in subjects with mild to moderate AD at 12 weeks.

Exploratory Objectives:

1.       To evaluate the efficacy of MK-7622 at 12 and 24 weeks as adjunct therapy to donepezil in subjects with mild to moderate AD on:

a.       Global Function as assessed by the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC)

b.      Cognition as assessed by the Composite Cognition Score-2 Domain, Mini-Mental Status Examination, and the Delayed Recall subtest of the ADAS-Cog12, Trail Making Test, Digist Span, Digit Symbol-Coding, and Verbal Fluency test

c.       Behavioral disturbance as assessed by the Neuropsychiatric Inventory (NPI)

2.       To assess the relationship between MK-7622 treatment effects (cognition, as assessed by ADAS-Cog11) and apolipoprotein E (APOE) genotype.

3.       To evaluate the pharmacokinetics of MK-7622 and its N-oxide metabolite in a subject population, and to enable the characterization of the pharmacokinetic/pharmacodynamic (PK/PD) and pharmacokinetic/adverse event (PK/AE) relationships. Additional, yet to be identified, metabolites may also be evaluated.

Principal Investigator: Edward Zamrini
Department: Alzheimer's Center
Co Investigator: Norman Foster
Co Investigator: Kevin Duff
Co Investigator: Richard King
Co Investigator: Dustin Hammers

Contact Information

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

Inclusion Criteria

Subject Inclusion Criteria

In order to be eligible for participation in this trial, the subject must:

1.       Be male or female and be between the ages of 55 and 85 years of age (inclusive) on the day of signing informed consent.

2.       Meet the criteria for a diagnosis of probable AD based on both a) the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

3.       Have a MMSE score ≥ 12 to ≤ 24 at Screening, as confirmed by a centralized rating vendor. If a subject is on a prohibited medication(s), the subject must wash off the medication(s) prior to this administration.

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) confirmed by an informant who knows the subject well.

5.       Each subject must have a magnetic resonance imaging (MRI) scan (1.5 or 3.0 Tesla) at Screening that is consistent with the diagnosis of AD. MRI scans will be analyzed by a central MRI reader. An MRI that was done within 3 months before the Screening visit that is available for review by the central MRI reading vendor is also acceptable provided the results are consistent with the diagnosis of AD.

6.       Be on a stable daily dose of 10 mg donepezil, 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. Twice daily doses of 5 mg are also acceptable. (The 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/trial partner must agree that they do not plan to discontinue treatment or initiate additional AD treatments during the trial unless medically necessary.

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

8.       Based on the PI’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 videotaping/audiotaping of selected interviews/assessments.

9.       Sign the informed consent after the trial has been explained to them, and before Screening assessments. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.

10.   Have a reliable and competent caregiver/trial partner who must have a close relationship with the subject, have face to face contact as least three days a week for a minimum of six waking hours a week, be willing to accompany the subject to all trial visits, and be willing to monitor compliance of the administration of the trial medication. The caregiver/trial partner should understand the trial and adhere to trial requirements (e.g., dose, visit schedules, and evaluations). The caregiver/trial partner should also be willing to participate in assessments that require caregiver/trial partner input (e.g., ADCS-ADL and the ADCS-CGIC). Note: For caregiver/trial partners who do not live with the subject, there must be significant ongoing interaction with the subject such as frequent telephone contacts in addition to face to face contact.  Sponsor should be contacted for consultation and approval of a caregiver/trial partner communication plan.

11.   Have a caregiver/trial partner that is willing to sign their own informed consent, after the trial has been explained to them, and before Screening assessments.

12.   Have results of clinical laboratory tests (complete blood count [CBC], blood chemistries, and urinalysis) within normal limits (or clinically acceptable to the PI) and which do not meet Exclusion Criteria #10 and #11 at Screening.

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

14.   If female, not be of childbearing potential as indicated by one of the following:

a.       Has reached natural menopause (defined as ≥ 46 years of age with either

                                                               i.      ≥ 12 months of spontaneous amenorrhea or

                                                             ii.       ≥ 6 months of spontaneous amenorrhea with serum 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.      Has had a hysterectomy;

c.       Has had a bilateral tube ligation; or

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

15.   Be willing to provide a sample for APOE genotyping.

Criteria to be assessed at Visit 3, prior to randomization:

16.       Continues to fulfill all of the Inclusion Criteria previously assessed at Visit 1.

 

Exclusion Criteria

Caregiver/Study Partner Exclusion Criteria:

Although Caregivers/Study Partners are not counted in the enrollment numbers as "subjects", there are reasons why a caregiver may not be able to participate in the trial:

  • Caregiver does not have a close relationship with the subject with AD.
  • Caregiver does not see him/her at least 3 days each week for a minimum of 6 waking hours each week.
  • Caregiver is unwilling or unable to go to all of the trial visits with him/her.
  • Caregiver is unwilling or unable to ensure that he/she takes the trial drug as instructed, and follow all of the trial requirements.
  • Caregiver is unable or unwilling to answer questions about the AD subject’s daily living activities, and his/her ability to understand, reason and make judgments.
  • Caregiver is unable or unwilling to follow all of the requirements of the trial as they pertain to your participation, or unwilling to consent to audio recording of selected interviews.

Subject Exclusion Criteria

The subject must be excluded from participating in the trial if the subject:

1.       Has a Rosen-modified Hachinski Ischemia Scale (MHIS) score > 4 at Screening (i.e., evidence of vascular dementia).

2.       Has a known history of stroke or structural changes on screening MRI scan that are clinically important in the PI’s opinion, including signs indicative of vascular dementia, large infarct, lacunes in critical areas, space-occupying lesions, or extensive white matter disease.

3.       Has evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., 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.

4.       Has a history of seizures or epilepsy within the last five years before Screening.

5.       Has evidence of a clinically relevant or unstable psychiatric disorder, based on the DSM-IV-TR criteria, including schizophrenia or other psychotic disorder, bipolar disorder, major depression, substance abuse disorders, or delirium. Major depression in remission for >2 years is not exclusionary.

6.       Has evidence of a current episode of major depression based on PI’s judgment. A score on the 15-item Geriatric Depression Scale (GDS) 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.       Is at imminent risk of self-harm, based on clinical interview and responses on the CSSRS, or of harm to others in the opinion of the PI. Subjects must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g. positive response to Items 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past two months, or suicidal behavior in the past six months.

8.       Has a history of alcoholism or drug dependency/abuse within the last 5 years of Screening.

9.       Is unwilling or not eligible (e.g., metal implants, obesity) to undergo an MRI scan at the Screening Visit (see the MRI procedure manual and imaging charter for details).

10.   Has one or more of the following laboratory findings:

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

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

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

Should a liver function test (LFT) be abnormal (ALT/AST > ULN but < 3x ULN, T-BIL > ULN but < 1.5x ULN) at Screening but not meet the specified criteria, the PI should attempt to characterize at entry the reason(s) for the elevation (e.g., alcohol abuse, metabolic syndrome with fatty liver, etc.). Subjects with suspected Gilbert’s Syndrome who have isolated T-BILI ≥ 1.5x ULN may enter the trial upon genetic confirmation (e.g., uridine disphosphate glucuronosyltransferase 1A1 [UGT1A1] assessment).

11.   Has an estimated creatinine clearance of less than 50 mL/min, OR estimated creatinine clearance between 40 and 50 mL/min inclusive along with actual creatinine clearance (by 24-hour urine collection before randomization) of < 50 mL/min:

a.       For Males: Creatinine Clearance = (140 – Age[yr]) x Weight (kg) serum creatinine (mg/dL) x 72

b.      For Females: Creatinine Clearance = 0.85 x (140 – Age[yr]) x Weight (kg) serum creatinine (mg/dL) x 72

NOTE: A 24-hour creatinine clearance sample may be obtained and analyzed prior to randomization for subjects who have estimated creatinine clearance values of 40-50 mL/min, both inclusive. In this case, only subjects with creatinine clearance values ≥50 mL/min confirmed via 24-hour sampling will be considered for randomization at V3.

12.   Has at least one of the following:

a.       Clinically significant vitamin B12 deficiency, or increased thyroid stimulating hormone [TSH], in the six months immediately before Screening, or  Vitamin B12 deficiency at Screening as determined by central laboratory normal values. (Treated B12 deficiency is allowed if stable normal levels on treatment), or

b.      Abnormally elevated TSH as determined by central laboratory normal values.

13.   Has a history of hepatitis or liver disease that, in the opinion of the PI, has been active within the six months prior to Screening.

14.   Has a recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening (such as, but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis) where participation in the trial would pose a significant medical risk to the subject. 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, 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 Visit 3.

15.   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, as determined by an ECG read by a central ECG vendor.

16.   Has a history of malignancy occurring within the five years immediately before Screening, except for a subject who had been adequately treated for:

a.       Basal cell or squamous cell skin cancer,

b.      In situ cervical cancer, or

c.       Localized prostate carcinoma, or

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

17.   Has donated blood products or has had phlebotomy of > 300 mL within 8 weeks of signing the informed consent, or intends to donate or receive blood products during participation in the trial.

18.   Has had major surgery, (for example: abdominal, thoracic, cardiac or orthopedic surgery, or any procedure requiring general anesthesia) within 3 months prior to Screening.

19.   Is currently participating in another investigational trial, or previously participated in another investigational trial (including any Merck & Co. Inc. studies) within 3 months prior to Screening.

20.   Is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this trial.

21.   Is pregnant, is attempting to become pregnant, or is nursing children.

22.   Is unable to meet medication washout requirements prior to Visit 2, as listed in Table 3. See Section 5.5 and 7.1.5.1 for additional details.

23.   Anticipates receiving any of the medications listed in Table 3 during the current trial.

 

Criteria to be assessed at Visit 3, prior to randomization:

24.   Meets any Exclusion criteria previously assessed at Visit 1.

25.   Is unable to tolerate trial medication from Visit 2 to Visit 3.

26.   Has less than a 75% drug compliance rate for trial medication taken from Visit 2 to Visit 3, as assessed by a standard pill count.