E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 |
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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. |
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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. |
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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 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. Mild to moderate white matter disease and up to 2 lacunar infarcts are acceptable. All patients will have a Baseline MRI as part of this study thus, if no previous images have been obtained the baseline MRI may be used for this purpose; 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 postmenopausal and men, ages 45 to 90. 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 |
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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 major 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 > 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 (confirmatory Western Blot). i)Patients at screening having a QTc interval > 450ms or uncontrolled arrhythmia or frequent PVC's (>5/minute) or Mobitz Type II second or third 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 Baseline c)Patients that required medications for agitation or psychotic features within 3 months prior to Baseline (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 Baseline. Low dose anxiolytics pre-medications prior to diagnostic testing is allowed. e)Patients taking illicit drugs or narcotics within 30 days of Baseline 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is safety and tolerability. |
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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 | 7 |
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 |
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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
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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 |