| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
|
| 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 safety and tolerability of BMS-708163 in patients with mild to moderate Alzheimer’s disease. |
|
| E.2.2 | Secondary objectives of the trial |
1)Characterize pharmacodynamic effects of BMS-708163 on
a)CSF biomarkers of mechanism of action (Aβ40, Aβ42) & putative biomarkers of neurodegeneration in AD (total Tau, phosphorylated Tau) in a subset of patients
b)Cognition as assessed with 11-item ADAS-cog, ADAS-cog memory score, executive function score (Color Trails Tests, Category & Letter Fluency Tests, Digit Span - forwards and backwards), a derived Global Cognition score (summary z-score), & Mini Mental State Exam
c)Function in daily living as assessed with Alzheimer’s Disease Cooperative Study - Activities of Daily Living scale
d)Global clinical impression as assessed with Clinical Dementia Rating-Sum of Boxes (CDR-SB) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) Patients (or legally acceptable representative as required by the IRB/IEC) and
their study partners have provided a written signed informed consent form/forms
(IRB/EC specific) prior to the initiation of any protocol required procedures.
b) For sites participating in intensive PK testing an additional signed written consent
by the patients and their study partners has been obtained prior to the initiation of
any intensive PK testing specified in Protocol Section 6.5.2.
2) Target Population
a) Patients at screening are required to satisfy the criteria for the clinical diagnosis of
probable Alzheimer’s disease based on NINCDS-ADRDA and DSM-IV-TR
criteria (294.1x Dementia of the Alzheimer Type) of mild to moderate disease
severity as determined by a MMSE32score of 16 to 26 inclusive.
b) Patients’ documented cognitive decline began at least 6 months prior to screening.
c) Patients currently being maintained on approved marketed medications for AD
are required to be on stable doses for at least 2 months prior to screening and the
study physician does not anticipate any modifications during the study including
the washout phase (however, patients who change AD medications during the
study will be allowed to continue).
d) Patients that are not going to be maintained on approved marketed medications
for AD should be free of such medications for at least 2 months prior to screening
with no plans to start such medications during the study, including the washout
phase.
e) Patients have had either CT or MRI imaging of the brain within 12-months prior
to baseline that is either normal or demonstrates atrophy consistent with an
Alzheimer’s disease diagnosis. Mild to moderate white matter disease and up to
2 lacunar infarcts are acceptable if not deemed to contribute significantly to the
patient’s dementia. In the event that no brain images have been obtained within
12 months prior to baseline, the baseline MRI may be used for this purpose (to be
performed 1 - 3 weeks prior to randomization).
f) Patients have a score of ≤ 4 on the Modified Hachinski Ischemia Scale (MHIS)29
at screening.
g) Patients are determined by the investigator to be medically stable at baseline as
determined by medical history, physical examination, laboratory results, and
electrocardiogram testing. Patients are physically able and expected to complete
the trial as designed.
h) Patients have a minimum of 6 years of education and were able to read, write and
communicate effectively during the premorbid state.
i) Patients and their study partners have adequate hearing, vision, and language
skills to perform neuropsychiatric testing and interviews as specified in the
protocol.
j) Patients are able to ingest oral capsules.
k) Patients have reliable study partners. The study partners are required to ensure
proper storage and administration of study medication and study procedures. A
reliable study partner is defined as minimally having 10 hours-week of direct
patient contact and being able to fulfill their study specified obligations based on
the investigator’s assessment.
l) Patients and their study partners must be able to understand and agree to comply
with the prescribed dosage regimens and procedures; report for regularly
scheduled office visits; and reliably communicate with study personnel about
adverse events and concomitant medications.
3) Age and Sex
a) Patients may be either male or female and between the ages of 50 - 90 inclusive. |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP
WOCBP include any female who has experienced menarche and who is not
postmenopausal. Post menopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
> 21.7 mIU/mL
Women who are using oral contraceptives, other hormonal contraceptives
(vaginal products, skin patches, or implanted or injectable products), or
mechanical products such as an intrauterine device or barrier methods
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing
abstinence or where their partner is sterile (eg, vasectomy) should be considered
to be of childbearing potential and are required to be excluded from the study.
b) Sexually active fertile men not using effective birth control if their sexual partners
are WOCBP.
2) Target Disease Exceptions
a) Patients with a medical condition other than Alzheimer’s disease that could
explain or contribute significantly to the patients dementia: eg, Down Syndrome,
abnormal thyroid function, posttraumatic conditions, syphilis, multiple sclerosis
or another disorder of neuro-inflammation, Parkinson’s disease, multi-infarct
dementia, Huntington’s disease, normal pressure hydrocephalus, CNS tumor,
frontotemporal dementia seizure disorder (other than childhood febrile seizures)
and subdural hematoma.
3) Medical History and Concurrent Diseases
a) Patients having a history of stroke (Note: Patient with a history of TIA may be
enrolled, if it occurred at least 3 months prior to screening and they are prescribed
appropriate treatment [eg, platelet aggregation inhibitors]).
b) Patients who are immunocompromised at screening including taking medications
that are systemic immunosuppressive treatment such as oral corticosteroids.
c) Patients at screening with a current diagnosis of active, peptic ulceration or
gastrointestinal bleeding within the last year and/or chronic inflammatory bowel
disease.
d) Positive Fecal Immunochemical Test (FIT™) at screening (unless subsequent
upper and lower GI work-up is negative for GI pathology).
e) Patients at screening having chronic or frequent episodes of diarrhea or loose
stools.
f) Patients at screening that have had any gastrointestinal surgery that could impact
upon the absorption of study drug.
g) Patients having a Vitamin B12 or folate deficiency (Note: Patients with a B12
deficiency may participate in the study if they are on stable Vitamin B12
replacement for at least 3 months prior to screening and their B12 levels are
within normal limits prior to randomization).
h) Patients having a hematologic or solid malignancy diagnoses within 5 years prior
to screening (Note: Patients with localized skin cancer, basal cell or squamous
cell carcinoma, may be enrolled in the study).
i) Patients having a Geriatric Depression Scale (GDS, 15-score short version)30
score of ≥ 6 at screening.
j) Patients that have had any unstable cardiovascular (includes uncontrolled
hypertension), pulmonary, gastrointestinal, or hepatic disease within 1 month
(30 days) prior to screening.
k) Patients having end-stage cardiovascular disease at screening (eg, CHF NYHA
Class III or IV or unstable angina).
l) Patients that have been treated or have had a lifetime diagnosis of schizophrenia
or bipolar disorder or have had a major depressive episode within the past
6 months prior to screening.
m) Patients having a history of neurosyphilis (as indicated by a positive screening
RPR test and a positive confirmatory test).
n) Patients having a history of drug or alcohol abuse within 12 months prior to
screening as defined by DSM-IV-TR criteria.
4) Physical and Laboratory Test Findings
a) Patients having uncontrolled hypertension at screening (eg, repeated diastolic
measurements ≥ 96 mmHg).
b) Patients having a diagnosis of hypothyroidism as indicated by a screening TSH
greater than the upper limit of normal and Free T4 Index less than the lower limit
of normal (Note: Patients with history of hypothyroidism may participate in the
study, provided they are euthryoid on stable thyroid replacement therapy for at
least 3 months prior to screening).
c) Patients having either of the following hepatic test abnormalities at screening:
i) AST or ALT greater than 1.5 times the upper limit of normal.
ii) Total Bilirubin greater than 2 times the upper limit of normal.
d) Patients having P-Amylase or Lipase values greater than 2 times upper limit of
normal at screening.
e) Patients at screening having insulin-dependent diabetes mellitus or HbA1C
> 7.5%.
Refer to protocol section 4.2.2 for additional exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is safety and tolerability. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| 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.8.3 |
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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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