Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease

Study Overview
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Brief Summary
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A phase 2, double-blind, randomized, placebo-controlled clinical trial to evaluate the safety and efficacy of Allopregnanolone as a regenerative therapeutic for Alzheimer's disease.

Detailed Description
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This is a proof-of-concept phase 2 clinical trial to investigate the long-term safety and efficacy of Allo to function as a regenerative therapeutic to restore structural integrity and cognitive function of the brain in participants with mild Alzheimer's disease (AD) dementia. Study participants will be male and female, APOE ε4 positive diagnosed with probable AD, Mini-Mental State Exam (MMSE) 20 to 26, ages 55 to 80 years old. After a 2-4-week screening period, participants will be randomized to 4 mg Allo (administered intravenously over 30 minutes, once per week, in clinic) or matching placebo, 1:1 allocation, for a period of 12 months. After 12 months, all participants in the placebo group will be crossed-over to receive Allo for the remainder of the study (6 month open-label phase). Brain imaging to evaluate the primary endpoint will be conducted at baseline, 6 and 12 months.

Official Title
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Safety and Efficacy of Allopregnanolone (Allo) as a Regenerative Therapeutic for Alzheimer's Disease: Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Clinical Trial

Conditions
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Alzheimer Dementia, Late Onset Alzheimer Disease, Neurodegenerative Diseases

Intervention / Treatment
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* Drug: Allopregnanolone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and postmenopausal women Age 55 to 80 years old Meets NIA-AA criteria for probable AD dementia MMSE of 20-26 APOE ε4 positive Geriatric Depression Scale short form (GDS-S) score of ≤ 6 No medical contraindications to participation Capacity to provide informed consent at screening Exclusion Criteria: Dementia other than probable AD Use of benzodiazepines, anticonvulsants, antipsychotics, or other drugs that might interact with the GABA-A receptor complex History of stroke with a modified Hachinski Ischemic Scale score >4 History of seizure disorder, focal brain lesion, traumatic brain injury History within the last 5 years of a primary or recurrent malignant disease Unstable or clinically significant cardiovascular, kidney or liver disease MRI indicative of any other significant abnormality, including but not limited to one or more significant ARIA-E or macro-hemorrhage findings, or multiple microhemorrhages (>8), or Fazekas score of 3; encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions Any conditions that would contraindicate MRI studies.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to the active intervention or placebo in parallel for 12 months. After 12 months, all participants in the placebo group will be crossed-over to receive Allo for the remainder of the study (6 month open-label phase).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allo group<br>Allopregnanolone 4mg IV 30-minute infusion once per week for 12 months. | Drug: Allopregnanolone<br>* Allopregnanolone 4mg IV via 30-minute infusion, once per week.<br>* Other names: Allo;|
| Placebo Comparator: Control group<br>Placebo (normal saline) IV 30-minute infusion once per week for 12 months. | Other: Placebo<br>* Normal saline solution IV via 30-minute infusion, once per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hippocampal volume | mm3 | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cambridge Cognition's Paired Associates Learning Test | Total errors score (adjusted) - number of errors made by the participant (range: 0 to  120). Higher scores indicate poor performance. | Baseline to 12 months | 
| Cambridge Neuropsychological Test Automated Battery (CANTAB) | Composite score (higher score indicate better outcome) | Baseline to 12 months | 
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11 | Total score (range 0 to 70); higher scores indicate poor performance. | Baseline to 12 months | 
| Alzheimer's Disease Cooperative Study (ADCS) Instrumental Activities of Daily (iADL) Living (iADL) | iADL subscore (range 0-56): Lower score indicates greater severity | Baseline to 12 months | 
| Safety and tolerability | Frequency of adverse events and serious adverse events | Baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mild Alzheimer Disease, Regenerative Therapeutic, APOE ε4, Neurogenesis, Allopregnanolone