Alzheimer Disease, Mild Cognitive Impairment
Conditions
Keywords
Alzheimer's disease, Mild Cognitive Impairment, Dementia, Regenerative therapeutic
Brief summary
The purpose of this study is to evaluate the safety and tolerability of allopregnanolone, a naturally occurring brain steroid, in mild cognitive impairment and early Alzheimer's disease participants. The primary goal is to determine the maximally tolerated dose.
Detailed description
1\) Each dose group will be comprised of 8 participants (6 randomized to allopregnanolone; 2 randomized to placebo) administered one dose of allopregnanolone or placebo once per week for 12 weeks. A higher dose will be administered to the next group of participants when the lower dose is shown to be safe and tolerable. 2) Pharmacokinetic analyses will be conducted on blood samples taken from participants at the beginning and end of the trial. 3) The trial will assess safety including via MRI brain imaging.
Interventions
DRUGAllopregnanolone injection (intravenous solution)
Allopregnanolone intravenous infusion
DRUGPlacebo injection (intravenous solution)
Placebo intravenous infusion
Sponsors
National Institute on Aging (NIA)
University of Southern California
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men or postmenopausal women * 55 years of age or older * Diagnosis of MCI due to AD or mild AD * MMSE \> 20 at screen * Capacity to provide informed consent * Residing in the community with a caregiver able to accompany the patient to clinic visits * No medical contraindications to participation * Willingness to comply with study procedures
Exclusion criteria
* Use of benzodiazepines, sedative/hypnotics, anticonvulsants, antipsychotics, and other drugs that might interact with the GABA-A receptor complex * Seizure disorder, history of stroke, focal brain lesion, traumatic brain injury, substance abuse, malignancy * Clinically significant laboratory or ECG abnormality * MRI indicative of any other significant abnormality, including but not limited to evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions * Any condition that would contraindicate an MRI such as the presence of metallic objects in the eyes, skin, heart, or body
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety profile: Adverse events | From Baseline to week 16 | Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm. |
| Safety profile: Clinical laboratory measurements | From Baseline to week 13 | Evaluating the proportion of subjects exceeding pre-established critical values per treatment arm: Alanine aminotransferase (ALT, U/L) \> 5 times upper normal limit Aspartate aminotransferase (AST, U/L) \> 5 times upper normal limit Total serum bilirubin (mg/dl) \> 2 times upper normal limit Serum creatinine (mg/dl) \> 2 times upper normal limit Serum creatine phosphokinase (U/L) \> 5 times upper normal limit |
| Safety profile: ARIA | From Baseline to week 13 | MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA |
| Safety profile: Physical and neurological examination | From Baseline to week 16 | To evaluate the proportion of abnormal examination findings of subjects in each treatment arm. |
| Tolerability - Maximum tolerated dose (MTD) | From Baseline to week 12 | Onset of sedation will define the upper most limit of drug dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState) | Baseline to Week 13 | Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState) |
| Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax) | Weeks: 1 and 12 | Measurement of maximum concentration |
| Brain MRI volumetrics | Baseline and Week 13 | Gray matter, white matter and hippocampal volume measurements, including subfield analysis. |
| Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax) | Weeks: 1 and 12 | Time to attain maximum concentration. |
| Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC) | Weeks: 1 and 12 | Pharmacokinetic parameter. |
| Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL) | Weeks: 1 and 12 | Pharmacokinetic parameter. |
| Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss) | Weeks: 1 and 12 | Pharmacokinetic parameter. |
Countries
United States
Outcome results
None listed