| 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 prodromal
Alzheimer’s Disease. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the predictive value and longitudinal behavior of CSF biomarkers (Aβ40,
Aβ42, total Tau, phosphorylated Tau) and volumetric MRI during the 24 week
treatment phase and the 28 week follow-up phase.
• To prospectively characterize effects on the following assessments as part of the
natural course (in placebo patients) and potential impact of BMS-708163:
− Assess for drug effects on progression to dementia (based on confirmed
progression using DSM-IV criteria).
− Global clinical impression as assessed with the Clinical Dementia Rating-Sum of
Boxes (CDR-SB), an instrument designed to measure the severity of cognitive
symptoms in daily life.
• To assess Notch-mediated (safety related) effects of BMS-708163 on:
− TFF3 plasma concentrations and its association with gastrointestinal safety
signals.
− Lymphocyte mRNA levels of HES-1 and its association with clinical safety signals.
− The immune system (lymphocyte subpopulations; immunoglobulin serum levels). |
|
| 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.
2) Target Population
a) Patient meets prodromal Alzheimer’s disease criteria as defined by:
i) Memory complaint by subject or study partner that is verified by a study partner.
ii) Abnormal memory function documented by scoring below the education
adjusted cutoff on the Logical Memory II subscale (Delayed Paragraph
Recall) from the Wechsler Memory Scale – Revised (the maximum score is 25):
(1) less than or equal to 8 for 16 or more years of education.
(2) less than or equal to 4 for 8 - 15 years of education.
(3) less than or equal to 2 for 0 - 7 years of education.
b) CSF Aβ42 levels below 200 pg/mL (note: patients who meet all other
inclusion/exclusion criteria and have a CSF Aβ42 level of ≥200, may be eligible
to be followed in a non-randomized, observational cohort to assess progression
rates [see Protocol Section 6.4.3.6]);
c) Mini-Mental State Exam score between 24 and 30 (inclusive);
d) Clinical Dementia Rating global score = 0.5. Memory Box score must be at least
0.5;
e) Patient has had either a CT or MRI brain imaging during the screening period that
is consistent with an Alzheimer’s disease pathology;
f) Patient has a score of ≤ 4 on the Modified Hachinski Scale (MHIS) at screening;
g) Patient is not currently being treated with approved marketed medications for AD
or if currently being treated is required to be on stable dose for at least 3 months
prior to screening and the study physician does not anticipate any modifications
during the study including the Follow-up phase (treatment with memantine is not
allowed during either the screening or treatment period);
h) Patients that are not going to be maintained on approved marketed medications
for AD should be free of such medications for at least 3 months prior to screening
with no plans to start such medications during the study, including the Follow-up
phase;
i) 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;
j) Patients have a minimum of 6 years of education and were able to read, write and
communicate effectively during the premorbid state;
k) Patients and their study partners have adequate hearing, vision, and language
skills to perform neuropsychiatric testing and interviews as specified in the
protocol;
l) Patients are able to ingest oral capsules;
m) Patients have reliable study partners. A reliable study partner is defined as
minimally having 10 hours per week of direct patient contact and being able to
fulfill their study specified obligations based on the investigator’s assessment;
n) 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;
o) The following treatments will be allowed as long as they were at a stable dose for
at least 3 months prior to randomization: donepezil, galantamine, rivastigmine,
vitamin E, fish oil, or estrogen.
3) Age and Sex
a.) Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile) and men, ages 45 to 90. Women are considered surgically
sterile only if they have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy. 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 > 35 mIU/mL |
|
| E.4 | Principal exclusion criteria |
1)Sex and Reproductive Status
a)WOCBP
b)pregnant or breastfeeding Women
c)Women with a + pregnancy test on enrollment or prior to administration of
investigational product
d)Sexually active fertile men not using effective birth control if their partners are
WOCBP
2)Target Disease Exceptions
a)Patient’s diagnosed with Dementia per DSM-IV criteria
b)Patients with any other medical condition other than prodromal Alzheimer’s
disease that could explain the patients memory or cognitive deficits
3)Medical History and Concurrent Diseases
a)Patients with a history of stroke
b)Patient who are immunocompromised at screening including taking medications
that are systemic immunosuppressive treatment such as oral corticosteroids
c)Patients with a history of gastrointestinal illnesses including:
i)current diagnosis of active, peptic ulceration or gastrointestinal bleeding within the
last year &/or chronic inflammatory bowel disease, at screening
ii)history of any gastrointestinal surgery that could impact upon the absorption
of study drug
iii)positive FIT™ during Screening period
(unless subsequent upper and lower GI workup is negative for GI pathology);
iv)chronic or frequent episodes of loose stools
d)Patients with Vitamin B12 or folate deficiency
e)Patients with GDS score of ≥ 6 at screening
f)Patients with any unstable cardiovascular (includes uncontrolled hypertension),
pulmonary, gastrointestinal or hepatic disease within 30 days prior to screening
g)Patients who have been treated for or have had a diagnosis of schizophrenia or
Bipolar Disorder within 3 years, prior to screening
h)Patients who have had an active depressive episode within 6 months prior to
screening
i)Patients with a history of neurosyphilis
j)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(ULN) & Free T4 Index less than the lower limit
of normal
c)Patients having either of the following hepatic test abnormalities at screening:
i)AST or ALT > 1.5 x ULN
ii)Total Bilirubin > 2 x ULN
d)Patients having P-Amylase or Lipase values > 2 x ULN at screening
e)Patients at screening having insulin-dependent diabetes mellitus or HbA1C > 7.5%
f)Patients at screening having pathologic renal findings as defined by presence
of either of the following criteria:
i)Calculated GFR < 30 mL/min/1.73m² (Cockcroft-Gault formula for GFR estimate)
ii)Positive Urine protein dipstick test with a reflexive quantitative urine
protein/creatinine ratio greater than 0.2. The test maybe repeated once. In the
event of UTI, the test may be repeated once the UTI has resolved
g)Patients having at screening any of following hematologic abnormalities:
i)Hemoglobin < 10g/dL
ii)WBC < 3.0 x 10³/mm³
iii)Platelet count < 100,000/mm³
h)Patients at screening who are HIV positive
i)Patients at screening having QTc interval (Bazett's correction) > 450 ms or
uncontrolled arrhythmia or frequent PVCs (> 5/minute) or Mobitz Type II 2nd
or 3rd degree AV block or evidence of acute or subacute myocardial infarction
or ischemia
5)Allergies & Adverse Drug Reactions
Patients having a history of any significant drug allergy (such as anaphylaxis or
drug induced hepatotoxicity)
6)Prohibited Treatments &/or Therapies
a)Patients taking memantine or ginko biloba
b)Patients that have taken an agent with a primary mechanism of action related to
Aβ levels or function (eg, γ-secretase inhibitors, Aβ antibodies or vaccines
targeting beta-amyloid) within 12 months prior to screening
c)Patients that required medications for agitation or psychotic features within
3 months prior to screening (including all antipsychotic medications)
d)Patients that have received a new antidepressant, anxiolytic or sleep medication
not taken at a stable dose within 30 days prior to screening
e)Patients taking illicit drugs or narcotics within 30 days of screening or regularly
during the study (including morphine, codeine, hydromorphone, oxycodone)
f)Pg-p substrates with narrow therapeutic index, Digoxin
g)Substrates with metabolism highly dependent on CYP 2C9 & CYP 2C19 &
narrow therapeutic index: warfarin, phenytoin, phenobarbital, amitriptyline,
clomipramine, flurbiprofen, losartan & proguanil Diclofenac, ibuprofen &
piroxicam permitted at low doses, but prohibited at high chronic doses
h)Substrates with metabolism highly dependent on CYP2D6 & narrow therapeutic
index including desipramine, nortriptyline, flecainide, propafenon & metoprolol
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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 0 |
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