| 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 | 15.1 |
| 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 long term 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 of CSF biomarkers (Aβ40, and Aβ42, total Tau,
phosphorylated Tau) on progression to dementia. |
|
| 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) &
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 & 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 at least 1 of the 4 following
criteria:
(1) 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):
(a) less than or equal to 8 for 16 or more years of education.
(b) less than or equal to 4 for 8 - 15 years of education.
(c) less than or equal to 2 for 0 - 7 years of education. OR
(2) Free and Cued Selective Reminding Test (FCSRT) Total Recall score of ≤ 39 OR
(3) FCSRT Free Recall score of ≤ 24 OR
(4) FCSRT Delayed Free Recall score of ≤ 8.
b) CSF Aβ42 levels below 200 pg/mL or Total Tau / Aβ42 ratio of ≥ 0.39.
Additionally, patients who meet all other inclusion/exclusion criteria with the
exception of the CSF criteria above, may be eligible to be followed in a nonrandomized,observational cohort to
assess progression rates [see Section
6.4.4.8]);
c) Mini-Mental State Exam score between 24 and 30 (inclusive);
d) Clinical Dementia Rating global score must be = 0.5 at Screening and Baseline
and the Memory Box score must be at least 0.5 at both Screening and Baseline;
e) Patients must have an MRI performed during the screening period, prior to
randomization, to allow the results to be available at the baseline visit. Results
will be centrally read. To be eligible for the study the MRI results must:
i) Be normal (commensurate with age) or demonstrate atrophy consistent with
an Alzheimer’s disease diagnosis;
ii) Reveal no more than mild to moderate white matter disease;
iii) Up to 2 lacunar infarcts are acceptable however, no lacunes are permitted in
the anterior thalamus, genu of internal capsule, or basal forebrain;
iv) Reveal no cortical infarcts;
v) Reveal no more than four microbleeds. Note: if an MRI scanner with a field
strength > 1.5 T is used, a higher number of microbleeds will be acceptable
as determined by the central neuroradiologist.
vi) Reveal no single area of superficial siderosis (as defined by signal void
along the brain pial on GRE studies);
vii)Reveal no focal asymmetric lobar atrophy or other findings suggesting that the
primary cause of dementia is better attributed to a cause other than AD;
viii) Reveal no current or prior evidence of macrohemorrhages (> 10 mm);
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 Baseline & the study physician does not anticipate any modifications
during the study;
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 Baseline
with no plans to start such medications during the study;
i) Patients are determined by the investigator to be medically stable at baseline as
determined by medical history, physical examination, laboratory results, &
electrocardiogram testing. Patients are physically able & expected to complete
the trial as designed;
j) Patients have a minimum of 6 years of education & were able to read, write and
communicate effectively during the premorbid state;
k) Patients & their study partners have adequate hearing, vision, & language
skills to perform neuropsychiatric testing & 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 approximately 5 hours per week of direct patient contact &
being able to fulfill their study specified obligations (including being able to
reliably describe & assess changes in the patient’s condition) based on the
investigator’s assessment;
n) Patients & their study partners must be able to understand & agree to comply
with the prescribed dosage regimens & procedures; report for regularly
scheduled office visits; & reliably communicate with study personnel about
adverse events & 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, memantine, vitamin E, fish oil, or
estrogen. |
|
| E.4 | Principal exclusion criteria |
1)Sex & Reproductive Status
a)WOCBP
For purposes of this study, WOCBP include any female who has experienced
menarche & who is not postmenopausal. Post menopause is defined as
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods & on hormone replacement
therapy, a documented serum follicle stimulating hormone level
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
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 (eg, Vitamin
B12 or folate deficiency, abnormal thyroid function, posttraumatic conditions,
syphilis, multiple sclerosis or another disorder of neuro-inflammation,
Parkinson’s disease, vascular or multi-infarct dementia, Huntington’s disease,
normal pressure hydrocephalus, CNS tumor, progressive supranuclear palsy,
seizure disorder (other than childhood febrile seizures), subdural hematoma).
3)Medical History & Concurrent Diseases
a)Patients w/ a history of stroke (Note: Patients w/ history of TIA may be
enrolled, if occurred at least 3 months prior to screening & they are
prescribed appropriate treatment (eg, platelet aggregation inhibitors)
b)Patient who are immunocompromised at screening including taking medications
that are systemic immunosuppressive treatment such as oral corticosteroids;
c)Patients w/ a history of gastrointestinal illnesses including:
i)a current diagnosis of active, peptic ulceration or gastrointestinal bleeding
within the last year &/or chronic inflammatory bowel disease, at screening
ii)a history of any gastrointestinal surgery that could impact upon the absorption
of study drug
iii)a + Fecal Immunochemical Test during the Screening period;
(unless subsequent upper & lower GI workup is negative for GI pathology);
iv)chronic or frequent episodes of loose stools
d)Patients w/ a Vitamin B12 or folate deficiency (Patients w/ a B12
deficiency may participate in the study if they are on stable Vitamin B12
replacement for at least 3 months prior to screening & their B12 levels are
within normal limits prior to randomization.
e)Patients w/ a Geriatric Depression Scale score of ≥ 6 at screening.
f)Patient w/ 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 major depressive episode within 6 months prior
to screening;
i)Patients w/ a history of neurosyphilis (indicated by a positive RPR test &
confirmed by a positive FTA-ABS test).
j)Patients having a history of drug or alcohol abuse within 12 months prior to
screening as defined by DSM-IV-TR criteria.
k) Patients having a hematologic or solid malignancy diagnoses within 5 years prior
to screening (Note: Patients w/ a history of localized skin cancer, basal cell or
squamous cell carcinoma, may be enrolled in the study as long as they are cancer
free prior to randomization. Patients w/ other localized cancers (without
metastatic spread) who have previously completed their course of treatment more
than 2 years prior to baseline, are not currently receiving treatment & have
been in remission may be enrolled only if, in the opinion of the investigator, there
is no expectation for recurrence or further cancer treatment during the study
period. Antihormonal therapy (ie, tamoxifen) is allowed if the patient's cancer is
in remission & the patient in on maintenance therapy to reduce their risk of
recurrence;
l)Patients w/ active liver disease or a history of hepatic intolerance that in the
investigator’s judgment, is medically significant
m)Patients who have a history or evidence of any medical, neurologic or
psychological condition that would expose them to an undue risk of a significant
adverse event or interfere w/ assessments of safety & efficacy during the
course of the trial as determined by the clinical judgment of the investigator.
n)Unwilling or unable due to existing medical condition to have a MRI at protocol specified time points;
Refer to Prot. 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.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the treatment phase, every 2 weeks for the first 8 weeks, then monthly for the next 16 weeks and then every 12 weeks for the remainder of the study. In addition avagacestat treated patients will be seen for safety visits at 4 and 12 weeks post treatment, and will have a 24 week post treatment skin examination by a dermatologist. |
|
| E.5.2 | Secondary end point(s) |
| To assess the predictive value of CSF biomarkers (Aβ40, and Aβ42, total Tau, total Tau/Aβ42 ratio, phosphorylated Tau) on progression to dementia |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| CSF Biomarkers will be assessed at Baseline, Week 2 (optional) Week 24 and Week 104. Progression to dementia will be assessed on an ongoing basis at all scheduled visits |
|
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 3 |
| 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 | 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 |
| Canada |
| Denmark |
| Finland |
| France |
| Netherlands |
| Sweden |
| United States |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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