| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| mild to moderate Alzheimer's Disease |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 II - Primary Extension Trial Objectives:
1. To evaluate the safety and tolerability of MK-8931 in the long term treatment of mild to moderate Alzheimer’s Disease
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 in subjects administered MK-8931 for 24 months to that of subjects administered placebo for 18 months followed by MK-8931 for 6 months.
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| E.2.2 | Secondary objectives of the trial |
Part I: Secondary Trial Objectives:
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 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. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The substudies are embedded in the main-study protocol. The objectives are as follows:
• To assess the effect of two doses of MK-8931 on CSF total tau in subjects with mild to moderate AD included in the CSF substudy.
• To assess the effect of two doses of MK-8931 on cortical amyloid load assessed using an amyloid tracer and PET imaging in subjects with mild to moderate AD included in the PET substudy.
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| E.3 | Principal inclusion criteria |
PartI:
1.Each subject must be ≥ 55 to ≤ 85 yo at the first visit.
2.Each subject 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 (see Appendix 3) and b) the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM IV TR) criteria for AD.
3.Each subject must have an MMSE score ≥ 15 and ≤ 26 at Screening
4.Each subject must 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. Each subject must have an MRI scan at the Screening Visit that is consistent with a diagnosis of AD. MRI scans or head CT obtained at Screening or within 12 months before Screening (with Sponsor approval) are acceptable alternatives and must be submitted for central review.
6.Each subject must 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, medical food/supplement (eg Vitamin E), 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. Subjects may need to be on AD treatments in accordance with local requirements.
8.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 required trial visits, and be 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).
9.Each subject must 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.Each subject must have results of a physical examination, vital signs, and ECG within normal limits or clinically acceptable to the investigator at Screening.
11.Each female subject is not of childbearing potential as indicated by one of the following
1.has reached natural menopause (defined as 46 years of age with either
a.≥ 12 months of spontaneous amenorrhea or
b.≥ 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.
2. has had a hysterectomy;
3. has had a bilateral tubal ligation; or
4. has had a bilateral oophorectomy (with or without a hysterectomy) and greater than 6 weeks have passed since the surgery.
12.Each subject must be willing to provide a blood sample for APOE and HLA genotyping.
13.Based on the investigator's judgment, each subject is 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.Each subject (or legal representative) must sign theICF in accordance with local requirements, after the scope and nature of the investigation have been explained to them, and before Screening assessments.
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.
Part II: 1. have tolerated study medication and completed the initial 78-week period of the trial. Subjects who did not complete Part I of the study will not be permitted to continue in Part II. In addition, subjects who are less than 75% compliant with trial medication in Part I will require Sponsor approval to participate in Part II.
2.have a trial partner who is reliable and competent. It is recommended that the trial partner accompany the subject to all trial visits. (check additional info on protocol)
3.sign (or legal representative sign) the ICF in accordance with local requirements, after the scope and nature of the investigation have been explained.
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| E.4 | Principal exclusion criteria |
1. The subject has a Rosen-modified Hachinski Ischemia Score > 4 at Screening (ie, evidence of vascular dementia).
2. The subject has a known history of stroke or evidence from screening imaging scan (e.g. MRI scan or CT) that is clinically important in the investigator's opinion.
3. 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. The subject has a history of seizures or epilepsy within the last 5 years before Screening.
5. The subject has 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. The subject has 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. The subject is 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 or method (eg positive response to
items 4 or 5 in assessment of, suicidal ideation on the C-SSRS) in the past 2 months or suicidal behavior in the past 6 months.
8. The subject has a history of alcoholism or drug dependency/abuse within the last 5 years before Screening.
9. The subject does not have an MRI scan obtained within 12 months before Screening available for central review and is unwilling or not eligible to undergo an MRI scan (eg, metal implants, obesity) at the Screening Visit (see MRI Procedure Manual and Imaging Charter for details). Exception: A head CT scan obtained at Screening or within 12 months before Screening may be accepted for evaluation of the eligibility criteria on a case-by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the subject). The head CT must be suitable for central review.
10.The subject’s MRI scan obtained at Screening shows evidence of a neurological disorder other than probable AD or
- evidence of a prior macrohemorrhage,
- symptomatic vasogenic edema in the investigator’s judgment,
- > 3 lacunar infarcts over 10 mm each, or
- any other clinically significant finding that may account for their
cognitive impairment, including but not limited to: brain tumor, large or
strategically located cortical or subcortical infarct, or severe white matter disease equaling a rating of 3 on the age-related white matter changes (ARWMC) scale.
An MRI that was done within 12 months before the Screening visit that is available for review by the central MRI reading vendor is also acceptable for evaluation of the eligibility criteria. A head CT scan obtained at Screening or within 12 months before Screening may be accepted instead of MRI on a case-by-case basis, as approved by the Sponsor (e.g., when MRI is contraindicated for the subject).
11.The subject at Screening has
1. alanine aminotransferase (ALT) ≥ 3 x upper limit of normal (ULN), OR
2. aspartate aminotransferase (AST) ≥ 3 x ULN, OR
3. total bilirubin (T-BIL) ≥ 1.5 x ULN.
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).
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.The subject has a history of hepatitis or liver disease that, in the opinion of the investigator, has been active within the six months prior to Screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The two Coprimary Efficacy Endpoints for the trial are the:
1. change from Baseline score in the ADAS-Cog at Week 78 and
2. change from Baseline score in the ADCS-ADL at Week 78.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ADAS-Cog: Screening, Baseline, Week 13, 26, 39, 52, 65 and 78
ADCS-ADL: Baseline, Week 13, 26, 39, 52, 65 and 78
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| E.5.2 | Secondary end point(s) |
| The Key Secondary Efficacy Endpoint is the change from Baseline score in the CDR-SB at Week 78. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Screening, Week 26, 52 and 78 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Portugal |
| Spain |
| Turkey |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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