Subjects with probable Alzheimer's Disease and healthy voulunteers
Conditions
Interventions
Product Name: EVT 301
Product Code: RO4477478
Pharmaceutical Form: Capsule, hard
Current Sponsor code: EVT 301
Other descriptive name: RO4477478
Concentration unit: mg milligram(s)
Concentration type:
Sponsors
Evotec NeuroSciences GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria for elderly control subjects: 1. Male or naturally or surgically sterile female aged between 50- 80 years. 2. BMI (Body Mass Index) 18.0 – 32.0, body weight less than 100 kg. 3. Sufficient mental capacity to understand the nature of the trial and any potential risks of participating in it, and to provide voluntary Informed Consent. Ability to communicate satisfactorily with the investigator and to participate in the study, and to comply with the requirements of the entire trial. 4. Willingness to give written consent to participate after reading the Subject Information leaflet and the Consent Form, and after having the opportunity to discuss the trial with the investigator or his delegate. 5. Mini-Mental State Exam (MMSE) score of 27-30, inclusive. Inclusion criteria for Alzheimer´s patients: 1. Male or naturally or surgically sterile female aged between 50- 80 years. 2. BMI 18.0 – 32.0, body weight less than 100 kg. 3. Onset of dementia between the ages of 45 and 80 years. 4. Does not require nursing home care. Subject lives with a spouse or other caregiver. Subject has a designated caregiver, either spouse or other caregiver, who will take responsibility for ensuring the administration of the study medication, the completion of protocol-stipulated assessments, either directly or through proxy, and is willing to sign the Consent Form. Caregiver may be a spouse, sibling, other next-of-kin or a person otherwise close to the subject or a legal representative. 5. Diagnosis of probable AD, based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer´s Disease and related Disorders Association criteria for this diagnosis (NINCDS/ADRDA criteria) and fulfills the DSM-IV criteria for dementia of the Alzheimer type. 6. Modified Hachinski Ischemic Scale score of 4 at the maximum. 7. Co-operative, able to ingest oral medication, willing to complete all aspects of the study, and capable of doing so either alone or with the help of a responsible caregiver. 8. Able to sign a written Informed Consent for participation in the study co-signed by the patient’s next of kin or caregiver. 9. Willingness to give written consent to participate after reading the Subject Information leaflet and the Consent Form, and after having the opportunity to discuss the trial with the investigator or his/her delegate and the caregiver. Are the trial subjects under 18? Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Exclusion criteria for elderly control subjects: -Clinically relevant abnormal history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer. -History of Parkinson´s disease, any type of dementia, Alzheimer´s disease, Pick´s disease, Huntington´s disease, or Creutzfeldt-Jacob´s disease. -Any active disease of the gastrointestinal system, liver, or kidneys . -Presence of any acute or chronic illness or history of chronic illness not otherwise mentioned elsewhere and sufficient to invalidate the control subject´s participation in the trial or make it unnecessarily hazardous. -Evidence of systemic infection. -Current cognitive impairment due to drugs. -Presence or history of severe adverse reaction to any drug. -Concomitant medication that by the investigator´s judgement would interfere with the interpretation of the study assessments or constitute a hazard to the subject's safety -Blood pressure and heart rate in seated position at the screening examination outside the ranges 90-160 mmHg systolic, 40-95 mmHg diastolic; resting heart rate outside of 50-90 beats/min. -Positive test for hepatitis B, hepatitis C, HIV1 or HIV 2 at screening. -History of cancer in the past 2 years, except for treated, non-recurrent skin cancer. -Participation in a clinical trial with a pharmaceutical product within the previous 3 months -Any other medical condition not previously mentioned that could be expected to put the subject at special risk. Exclusion criteria for Alzheimer´s subjects: -History or clinical evidence of stroke, normal pressure hydrocephalus, subdural hematoma, intracranial mass, current seizure disorder (seizures within 1 year of screening or under treatment with an anticonvulsant drug), significant head trauma within 5 years of dementia diagnosis that resulted in unconsciousness and hospitalisation, or dementia with an onset immediately following heart surgery or cardiac arrest. -History of Parkinson´s disease, Pick´s disease, Huntington´s disease, or Creutzfeldt-Jacob´s disease. -Clinically relevant abnormal medical history, physical findings, ECG, or laboratory values at the pre-trial screening assessment that could interfere with the objectives of the trial or the safety of the volunteer. -History of abnormal liver function tests within one year. -Evidence of systemic infection. -Current cognitive impairment due to drugs. -Clinically important thyroid hormone abnormalities detected within 1 year of study entry unless these laboratory abnormalities have been treated for at least 3 months, and dementia has progressed post-treatment and during the 6 months prior to enrolment. -Clinically important folic acid or B?2 abnormalities detected within 1 year of study entry unless these laboratory abnormalities have been treated for at least 3 months, and dementia has progressed post-treatment and during the 6 months prior to enrolment. -Blood pressure and heart rate in seated position at the screening examination outside the ranges 90-160 mmHg systolic, 40-95 mmHg diastolic; resting heart rate outside of 50-90 beats/min. -Current evidence of pernicious anemia, history or current evidence of syphilitic brain disease or other chronic infections of the central nervous system. -Any active disease of the gastrointestinal system, liver, or kidneys that could result in altered absorption, excess accumulation, or impaired metabolism
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): The primary efficacy variable will be MAO-B occupancy in brain assessed with dynamic PET scanning with [11C]-L-deprenyl-D2 before and after different repeated doses of EVT 301. Regions of interest (ROIs) will be drawn for hippocampus, thalamus, caudate nucleus, putamen and frontal, temporal, parietal and occipital cortices.;Main Objective: - To determine a steady-state trough concentration level of EVT 301 in plasma producing a comparable extent of monoamine oxidase B (MAO-B) occupancy in brain, assessed with dynamic positron emission tomography (PET) with [11C]-L-deprenyl-D2, reflecting MAO-B enzyme inhibition, as the average extent of MAO-B occupancy achieved by selegiline 10 mg daily for 7-14 days in a separate group of subjects in this study. The effects of selegiline and EVT 301 will be compared in hippocampus, thalamus, caudate nucleus, putamen and frontal, temporal, parietal and occipital cortices. - To identify a daily dose level of EVT 301 that produces near-complete inhibition of MAO-B enzyme activity in brain, by performing non-linear regression analysis of plasma steady-state trough concentration and enzyme occupancy data and by computing estimates for enzyme occupancy at different dose levels. ;Secondary Objective: - pharmacokinetic steady-state for EVT 301 before the 2nd PET scan - confirmation of comparable inhibition of brain MAO-B by similar plasma steady-state trough concentrations of EVT 301 in patients with mild to moderate probable Alzheimer’s Disease (AD) and in elderly control subjects - the effect of 7-14 days treatment with EVT 301 on regional cerebral blood flow and comparison of this with the effect of 7-14 days treatment with selegiline in patients with AD and in elderly control subjects - the extent of MAO-B enzyme inhibition in blood platelets at different steady-state trough plasma concentrations and dose levels of EVT 301, and comparison of the effects of treatment with EVT 301 to those of treatment with selegi | — |
Countries
Finland
Outcome results
None listed