Protocol H8A-MC-LZAZ (a) / ADC-040-A4
Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4 Study)
Alzheimers disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline in cognitive function and ability to perform activities of daily living,and ultimately can lead to death due to complications of the disease. Pathologic hallmarks of AD identified at autopsy include the presence of neuritic amyloid-B (AB) plaques. The AB plaques are protein deposits that accumulate outside and around neurons. The AB hypothesis for AD, which states that the production and deposition of AB (later forming neuritic AB plaques) is an early and necessary event in the pathogenesis of AD, suggests that treatments that slow the synthesis or deposition of AB, or that increase clearance, might be expected to slow the progression of AD. One such treatment is immunotherapy. Solanezumab is a monoclonal antibody that is being developed as a passive immunization therapy to reduce AB burden. Converging evidence from both genetic at risk and age at risk cohorts suggests that the pathophysiological process of AD begins well more than a decade before the clinical stage now recognized as AD dementia, and that neurodegenerationis already apparent by the stage of Mild Cognitive Impairment (MCI) / prodromal AD. The A4 study will target those participants with evidence of brain amyloid pathology on PET amyloid imaging who are still clinically normal but at high risk for cognitive decline (defined as preclinical AD).Objectives: The primary objective of this study is to test the hypothesis that solanezumab, administered as an intravenous infusion at a dose of 400 mg every 4 weeks for 3 years, will slow the cognitive decline with placebo in participants with preclinical AD. Study Design: This is a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing 400-mg solanezumab with placebo given as infusions once every 4 weeks 3 years in approximately 1150 outpatients with preclinical AD. Diagnosis and Main Criteria for Inclusion and Exclusions: Participants will be males and females 65 to 85 years old with preclinical AD. The study population is defined as participants with preclinical AD who have an MMSE score between 25 and 30, a Logical Memory test, part IIa score between 6 and 18, and a global CDR of 0; and having screening florabetapir PET scan indicating brain amyloid pathology.Efficacy: Preclinical Alzheimer Cognitive Composite (ADCS-PACC)Primary Analysis: The primary endpoint ADCS-PACC will be analyzed using an MMRM analysis.
Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase I
Rationale: The first clinical trial to evaluate the safety and tolerability of allopregnanolone (Allo), a naturally occurring brain steroid, in mild cognitive impairment and Alzheimers disease participants. Allo is an investigational drug molecule shown in animal studies to stimulate the birth of new neurons, rescue cognition and lower indicators of Alzheimers disease. Objectives: 1) The first group of participants in the trial will be given one dose of Allo once per week for 12 weeks, only increasing the dose for the next group of participants when the lower dose has been shown to be safe. The primary goal is to determine the highest dose that is safe and tolerated by participants. 2) Analysis will also be done on blood samples taken from participants at the beginning and end of the trial to determine how the body responds to the drug molecule. 3) As per FDA requirements, the trial will investigate potential safety concerns including blood vessel changes via brain imaging. Secondary goals are to assess the short-term effects of Allo treatment on learning and memory as well as detect changes via MRI brain imaging to help researchers prepare for a larger-scale clinical trial. Study Population: The trial will enroll 24 participants (12 post-menopausal women, 12 men) diagnosed with mild cognitive impairment (MCI) or early Alzheimers disease. Participants must be 55 years of age or older, have a score on the Mini-Mental State Examination greater than 20, and be able to provide informed consent. Study Methodology: Participants will be given Allo or placebo intravenously once per week for 12 weeks. Description of Study Arms: Each dose (low to high) will have a separate, gender balanced group of 8 participants. 6 participants will be given Allo and 2 will be given placebo. At the end of the study, 18 participants will have received Allo and 6 will have received placebo. Endpoints: To determine the safety and tolerability of Allo, the trial will evaluate 1) if any, how much sedation after each dose of Allo; 2) if any, how many side-effects participants report; 3) any clinically significant changes in participants (for example: blood tests, weight, heart rate, heart monitor, brain scan, tests of memory) and 4) changes in brain imaging.
Exercise targeting cognitive impairment in Parkinsons disease
Mild cognitive impairment (MCI), particularly of the executive function (EF) subtype, is common in Parkinson's disease (PD) and transitions to dementia, increased fall risk, and poor quality of life. There is currently no effective treatment of MCI in PD. Our animal and clinical studies in PD demonstrate that skilled exercise facilitates neuroplasticity of the basal ganglia (BG), a brain region sub-serving EF and supports the hypothesis that exercise will reverse EF deficits in PD. Furthermore, recent studies in healthy aging support that skill-based exercise that specifically promotes motor skill fitness (MSF), compared with aerobic exercise that promotes cardiovascular fitness (CF), has a greater impact on EF and related BG circuits. The aim of this application is to compare and elucidate the effects of skill-based versus aerobic exercise versus control on MCI of the EF subtype in PD; we hypothesize that skill-based exercise will result in the greatest improvement in EF and lead to modification of underlying neural substrates. Individuals with PD and MCI will be assigned to 1 of 3 groups (N = 50/group) involving 36 1-hr sessions over 12 weeks including either: (i) skill-based exercise; (ii) aerobic exercise or (iii) social-contact control. Specific Aim 1 tests the hypothesis that skill-based exercise will lead to greater improvement in EF as indexed by standardized neurocognitive measures of EF. We will also compare pre-post exercise related changes on CF and EF. Secondary outcome measures will compare pre-post exercise effects on self- efficacy, quality of life (PDQ39) and Parkinson disease severity (MDS-UPDRS). Specific Aim 2 will test the hypothesis that skill-based will lead to greater gains in EF, compared to aerobic exercise or a control group on the ability to generalize task performance as indexed by a validated context-dependent motor learning (CDML) task. Specific Aim 3 will test the hypothesis that skill-based exercise will lead to greater gains in EF compared to aerobic exercise or a control group by examining improved Dual Task motor performance and the corresponding more efficient neural activity of brain regions sub-serving EF. DT capability will be performed during an fMRI scale. All assessments, that include motor skill and cardiovascular fitness, will be made at baseline and at 12 weeks (post-intervention); a 3-month follow up for EF in SA1 will be done.