Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD

Study Overview
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Brief Summary
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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
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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.

Official Title
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Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase 1

Conditions
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Mild Cognitive Impairment, Alzheimer Disease

Intervention / Treatment
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* Drug: Allopregnanolone injection (intravenous solution)
* Drug: Placebo injection (intravenous solution)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 55 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allopregnanolone 2 mg<br>Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks | Drug: Allopregnanolone injection (intravenous solution)<br>* Allopregnanolone intravenous infusion<br>* Other names: 3α-hydroxy-5α-pregnan-20-one;|
| Experimental: Allopregnanolone 4 mg<br>Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks | Drug: Allopregnanolone injection (intravenous solution)<br>* Allopregnanolone intravenous infusion<br>* Other names: 3α-hydroxy-5α-pregnan-20-one;|
| Experimental: Allopregnanolone 6-18 mg<br>Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks | Drug: Allopregnanolone injection (intravenous solution)<br>* Allopregnanolone intravenous infusion<br>* Other names: 3α-hydroxy-5α-pregnan-20-one;|
| Placebo Comparator: Placebo<br>Drug: Placebo injection (intravenous solution) once per week for 12 weeks | Drug: Placebo injection (intravenous solution)<br>* Placebo intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile: Adverse events | Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm. | From Baseline to week 16 | 
| Safety profile: Clinical laboratory measurements | 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 | From Baseline to week 13 | 
| Safety profile: ARIA | MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA | From Baseline to week 13 | 
| Safety profile: Physical and neurological examination | To evaluate the proportion of abnormal examination findings of subjects in each treatment arm. | From Baseline to week 16 | 
| Tolerability - Maximum tolerated dose (MTD) | Onset of sedation will define the upper most limit of drug dose | From Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax) | Measurement of maximum concentration | Weeks: 1 and 12 | 
| Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax) | Time to attain maximum concentration. | Weeks: 1 and 12 | 
| Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC) | Pharmacokinetic parameter. | Weeks: 1 and 12 | 
| Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL) | Pharmacokinetic parameter. | Weeks: 1 and 12 | 
| Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss) | Pharmacokinetic parameter. | Weeks: 1 and 12 | 
| Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState) | 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) | Baseline to Week 13 | 
| Brain MRI volumetrics | Gray matter, white matter and hippocampal volume measurements, including subfield analysis. | Baseline and Week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, Mild Cognitive Impairment, Dementia, Regenerative therapeutic