| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 17.1 |
| 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 |
|
| 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 |
To assess the efficacy of two doses of MK-8931 on cognition in sugjects with mild to moderate AD
To assess the efficacy of two doses of MK8931 on functional ability in activities of daily living in subjects with mild to moderate AD
To assess the safety and tolerability of two doses of MK-8931 in the treatment of subjects with mild to moderate AD
Extension Study:
To evaluate the safety and tolerability of MK8931 in the long term treatment of mild to moderate Alzheimer's Disease.
To compare the efficacy of MK8931 on cognition and functional ability in activities of daily living in subjects with mild to moderate AD in subjects administered MK8931 for 24 months to that of subjects adminitered placebo for 18 months followed by MK8931 for 6 months. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the overall clinical reposnse, as reflected by global assessment, of two doses of MK-8931 in subjects with mild to moderate AD
Extension:
To compare the efficacy of MK8931 adminstered for 18 months to that of subjects adminstered placebo for 18 months followed by long term treatment of MK8931 in extension on cognition, function, disease progression and health economic burden at multiple time points. |
|
| 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 |
There are three substudies;
1. A CSF Biomarker Substudy to evaluate changes in CSF concentrations of Aβ40, Aβ42, sAPPβ, total tau and phosphorylated tau (p-tau).
2. An Amyloid Imaging Substudy to Evaluate changes in Amyloid Load using PET and an Amyloid Tracer (Main cohort only)
3. Future Biomedical Research blood sample. To find out if there are differences between how different participants respond to the same drug. This can be done by studying the DNA found in the blood sample.
These substudies are part of the main protocol and as such have the same date and version as the main protocol
The following sites will conduct the optional CSF substudy (1);
Dr Bullock
Dr Ritchie
Dr Vanderputt
This substudy can involves all patients - both Safety Cohort and Main Cohort.
The following sites will conduct the optional PET substudy (2);
Dr Bullock
Dr Ritchie
Dr Vanderputt
Dr Jones
This substudy will start when the Main cohort starts.
All sites and all participants will be given the opportunity to be involved in the Future Biomedical Research sub study (3). |
|
| E.3 | Principal inclusion criteria |
Each subject must be ≥ 55 to ≤ 85 years of age at the first visit.
Each subject must 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.
Each subject must have an MMSE score ≥ 15 and ≤ 26 at Screening
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.
Each subject must have an MRI scan at the Screening Visit that is consistent with a diagnosis of AD.
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
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, 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/caregiver should
understand the nature of the trial and adhere to trial requirements (eg, dose, visit
schedules, and evaluations).
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 past since the surgery.
Each subject must be willing to provide a blood sample for APOE genotyping.
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.
Each subject (or legal representative) must sign the informed consent form 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.
Additional Inclusion Criterion for Safety Cohort
Each subject must have a reliable and competent trial partner/caregiver who has
a close relationship with the subject, has face to face contact at least five days a
week for a minimum of 10 waking hours a week, is willing to accompany the
subject to all 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). |
|
| E.4 | Principal exclusion criteria |
The subject has a Rosen-modified Hachinski Ischemia Score > 4 at Screening
The subject has evidence of a clinically relevant neurological disorder other than
the disease being studied (ie, probable AD) at Screening
The subject has evidence of a clinically relevant or unstable psychiatric disorder
The subject’s MRI scan obtained at Screening shows evidence of a neurological
disorder other than probable AD
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.
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.
The subject has a recent or ongoing, uncontrolled, clinically significant
medical condition within 3 months of the Screening Visit
The subject has a history or current evidence of long QT syndrome, QTC interval or torsades de pointes.
The subject has a history of malignancy occurring within the five years immediately before Screening
The subject has
1. clinically significant vitamin B12 or folate deficiency in the six months
immediately before Screening, or
2. vitamin B12 or folate deficiency in addition to increased serum
homocysteine or methylmelonic acid levels at Screening as determined by central laboratory normal values.
The subject anticipates receiving any of the treatments listed in Table 1 p58 pf the protocol, during the current trial.
The subject has a history of erythroderma (exfoliative dermatitis), DRESS
syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), Stevens-Johnson Syndrome or toxic epidermal necrolysis.
The subject has exudative (wet) age-related macular degeneration, active proliferative diabetic retinopathy, myopia or hyperopia, pigment dispersion syndrome, pseudo-exfoliation syndrome, pigmentary glaucoma, glaucoma that requires > 2 classes of medications, IOP > 21 mmHg, 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
The subject has a history of an ongoing medical condition that has been poorly
controlled within 6 months of the Screening Visit
The subject has history of congestive heart failure,
myocardial infarction, heart surgery, syncope, bradycardia, or clinically significant hypotension within one year immediately before Screening.
The subject has used warfarin within one month before Screening
The subject has used digoxin within one month before Screening.
The subject has used a strong P-glycoprotein (P-gp) inhibitor within one month before Screening.
The subject has trans-illumination defects of the iris, irregularly shaped pupil, or
cataract surgery within 6 months before Screening.
Additional Exclusion Criteria for the CSF Substudy
The subject has 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 the Amyloid PET Substudy
The subject has been exposed to ionizing radiation > 15 mSv in other research
studies within the last 12 months.
The subject has had any surgical or medical condition which might significantly
alter the distribution, metabolism, or excretion of [18F]PET tracer.
The subject has a Body Mass Index (BMI) under 18 or over 35 at the Screening
Visit.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. To assess the efficacy of two doses of MK8931 on congnition in subjects with mild to moderate Alzheimer's Disease
2. To assess the efficacy of two doses of MK8931 on functional ability in activities of daily living in subjects with mild to moderate Alzheimer's Disease
3. To assess the safety and tolerability of three doses of MK8931 in the treatment of subjects with mild to moderate Alzheimer's Disease
Extension Study:
To evaluate the safety and tolerability of MK8931 in the long term treatment of mild to moderate Alzheimer's Disease
To compare the efficacy of MK8931 on cognition and functional ability in activities of daily living in subjects with mild to moderate AD in subjects adminitered MK8931 for 24 months to that of subjects adminstered placebo for 18 months followed by MK8931 for 6 months.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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.
The two Coprimary Efficacy Endpoints for the extension trial are the;
1. change from Baseline score in the ADAS-Cog at week 104 and
2. change from Baseline score in the ADCS-ADL at week 104 |
|
| E.5.2 | Secondary end point(s) |
| To assess the overall clinical response, as reflected by global assessment, of two doses of MK8931 in subjects with mild to moderate Alzheimer's Disease. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The key secondary efficacy end point is the change from Baseline score in the CDR-SB at week 78.
Screening, week 26, 52 and 78. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Date the last patient completes the final study visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 19 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 19 |
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