The primary objective of the study is to assess the safety and tolerability of BMS-708163 in patients with prodromal Alzheimer*s disease.
ID
Source
Brief title
Condition
- Other condition
- Dementia and amnestic conditions
Synonym
Health condition
Milde geheugenstoornissen, amnestische stoornissen, prodromale stoornissen ziekte van Alzheimer
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome of the study is to evaluate if BMS-708163 is safe and well
tolerated.
Secondary outcome
The secondary outcomes of the study are to assess if BMS-708163 lowers Aβ40 and
Aβ42 in CSF and plasma and if it slows clinical progression.
Background summary
This is the second multiple-dose clinical trial experience with BMS-708163, a
GammaSecretase Inhibitor, in patients with AD. The first multiple dose study in
mild to moderate AD is ongoing. This study will evaluate and compare BMS-708163
125 mg/day versus placebo with regard to safety, tolerability, pharmacodynamic
and pharmacokinetic effects. The information from this study will be used
primarily to provide safety and tolerability data but will also serve to verify
biomarker inclusion criteria, assist in dose selection and inform sample size
estimates for a Phase 3 prodromal AD program using BMS-708163.
Dose selection for this study is based on the strategy of safely delivering
sufficient gamma secretase inhibition (reduction of brain Aβ concentrations)
while minimizing Notch inhibition. Since there is no clinical data to suggest
the minimum level of gamma-secretase inhibition that is necessary for clinical
efficacy, the upper range dose of 125 mg/day selected in this Phase 2 study is
based on safety. That is, the 125 mg/day dose of BMS-708163 yields a target
exposure that was associated with acceptable tolerability and safety in Phase 1
studies with an approximately > 50% reduction in CSF Aβ.
Study objective
The primary objective of the study is to assess the safety and tolerability of
BMS-708163 in patients with prodromal Alzheimer*s disease.
Study design
The study is a multi-center, randomized, double-blind, 2-arm,
placebo-controlled, 176 week, parallel-group study in patients with prodromal
Alzheimer*s disease to evaluate safety, tolerability, pharmacodynamic and
pharmacokinetic effects of once daily dosing of BMS-708163.
All patients will be randomly assigned in a double-blind manner to one of the
following treatment groups: placebo or 125 mg BMS-708163 once daily. All
patients will initially be treated with 50 mg for 2 weeks and then increased to
125 mg for the remainder of the treatment period.
Subjects who do not meet the CSF inclusion criteria (CSF Aβ42 < 200 pg/mL or
Total tau/Aβ42 ratio >= 0.39 ) but otherwise fulfill the study inclusion
criteria may continue to be followed for rating scale visits but will not be
randomized to any treatment arm. Approximately 100 patients will enter the
non-randomized observational group. Subjects in this non-randomized
observational cohort will serve to provide prospectively collected comparison
data regarding CSF cutoff values and progression to dementia rates. Once
subjects in this observation cohort progress to a diagnosis of dementia they
will be discontinued from the study and receive standard of care treatment.
Intervention
BMS-708163 is an investigational product in this study. All patients who meet
the study entry criteria will receive placebo or 125 mg BMS-708163 once daily.
Study burden and risks
Burden: study procedures (physical exams, blood sampling, MRI scan, lumbar
puncture, completing questionnaires) and regular attendance for hospital visits
during the treatment phase
Risks: possible adverse events of BMS-708163
Benefit: possibility that BMS-708163 slows down disease progression
Group relatedness: knowledge gain from this study may also help other patients
in the future
Vijzelmolenlaan 9
3447 GX Woerden
NL
Vijzelmolenlaan 9
3447 GX Woerden
NL
Listed location countries
Age
Inclusion criteria
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 2 following criteria: 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):
- less than or equal to 8 for 16 or more years of education.
- less than or equal to 4 for 8 - 15 years of education.
- less than or equal to 2 for 0 - 7 years of education OR Free and Cued Selective Reminding Test (FCSRT) Total score of <=39.
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 non-randomized, observational cohort to assess progression rates
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) If patients have had either CT or MRI imaging of the brain within 12 months prior to baseline, the results should either be normal or demonstrate atrophy consistent with an Alzheimer*s disease diagnosis;
f) Patient has a score of less or equal than 4 on the Modified Hachinski Scale (MHIS) at screening
g) Women who are postmenopausal and men, ages 45 to 90.
Exclusion criteria
a) Patient*s diagnosed with Dementia per DSM-IV criteria;
b) Patients with a history of gastrointestinal illnesses
c) Patients taking memantine or ginko biloba
d) Patients that have taken an agent with a primary mechanism of action related to Aβ levels or function (eg, gamma-secretase inhibitors, Aβ antibodies or vaccines targeting beta-amyloid) within 12 months prior to baseline.
e) Patients that required medications for agitation or psychotic features within 3 months prior to baseline (including all antipsychotic medications).
f) Patients that have received a new anxiolytic or sleep medication not taken at a stable dose within 30 days prior to baseline. Low dose anxiolytics pre-medications prior to diagnostic testing (e.g. neuroimaging, lumbar puncture, etc.) is allowed.
g) Pg-p substrates with narrow therapeutic index, Digoxin
h) Patients who have been treated for or have had a diagnosis of schizophrenia or Bipolar Disorder within 3 years, prior to screening
i) Patients who have had an active depressive episode within six months prior to screening
j) Patients with a history of neurosyphilis (indicated by a positive RPR test and confirmed by a positive FTA-ABS test)
k) Patients having a history of drug or alcohol abuse within 12 months prior to screening as defined by DSM-IV-TR criteria
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-010067-16-NL |
| ClinicalTrials.gov | NCT00890890 |
| CCMO | NL28084.028.09 |