Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease

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, 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 6 months. After 6 months, all participants in the placebo group will be crossed-over to receive Allo for the remainder of the study (3 month open-label phase). Brain imaging to evaluate the primary endpoint will be conducted at baseline, 3 and 6 months.

• Allopregnanolone (Drug), also known as Allo: Allopregnanolone 4mg IV via 30-minute infusion, once per week.
• Placebo (Other): Normal saline solution IV via 30-minute infusion, once per week

Primary outcomes

• Hippocampal volume [Baseline to 6 months]: mm3

Secondary outcomes

• Cambridge Cognition's Paired Associates Learning Test [Baseline to 6 months]: Total errors score (adjusted) - number of errors made by the participant (range: 0 to \~120). Higher scores indicate poor performance.
• Cambridge Neuropsychological Test Automated Battery (CANTAB) [Baseline to 6 months]: Composite score (higher score indicate better outcome)
• Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11 [Baseline to 6 months]: Total score (range 0 to 70); higher scores indicate poor performance.
• Alzheimer's Disease Cooperative Study (ADCS) Instrumental Activities of Daily (iADL) Living (iADL) [Baseline to 6 months]: iADL subscore (range 0-56): Lower score indicates greater severity
• Safety and tolerability [Baseline to 6 months]: Frequency of adverse events and serious adverse events

Other outcomes

• Other regional brain volumes [Baseline to 6 and 9 months]: Change in regional brain volumes (mm3)
• Diffusion tensor imaging (DTI) [Baseline to 6 and 9 months]: Change in white matter tract diffusion (scalar values and/or mm2/sec)
• Resting state functional MRI [Baseline to 6 and 9 months]: Change in functional connectivity (z transformed correlations)
• Arterial spin labeling (ASL) [Baseline to 6 and 9 months]: Change in regional cerebral blood flow (mL/100g)
• Exploratory blood based biomarkers [Baseline to 6 and 9 months]: Change from baseline in biomarkers of AD pathology, neurogenesis and inflammation
• Clinical Dementia Rating (CDR) [Baseline to 6 and 9 months]: Sum of boxes score (CDR-SB): range 0-18
• Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 14 [Baseline to 6 and 9 months]: Total score (range 0-90)
• Mini Mental State Examination (MMSE) [Baseline to 6 and 9 months]: Total score (range 0-30)
• Neuropsychiatric Inventory-Questionnaire (NPI-Q) [Baseline to 6 and 9 months]: Total score (range 0-36). Higher scores indicate greater symptom severity
• EuroQol 5-Dimension / 5-Level health-related quality of life scale scores (EQ-5D-5L) [Baseline to 6 and 9 months]: Reported as frequency, percentage and index value.
• Quality of Life in Alzheimer's Disease scale (QoL-AD) [Baseline to 6 and 9 months]: Total score (range 13-52). Higher score indicate better QoL
• Zarit Burden Interview (ZBI) [Baseline to 6 and 9 months]: Total score (range 0-48). Higher scores indicate high burden

Sex: All, ages: 55 Years to 80 Years

Main Inclusion Criteria:

* Men and postmenopausal women
* Age 55 to 80 years old
* Meets NIA-AA criteria for probable AD dementia
* MMSE of 20-26
* Plasma p-Tau217 positive
* Geriatric Depression Scale short form (GDS-S) score of ≤ 6
* No medical contraindications to participation
* Capacity to provide informed consent at screening

Main 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.
* No evidence of AD-like pattern of brain atrophy

• Raikes AC, Hernandez GD, Matthews DC, Lukic AS, Law M, Shi Y, Schneider LS, Brinton RD. Exploratory imaging outcomes of a phase 1b/2a clinical trial of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: Structural effects and functional connectivity outcomes. Alzheimers Dement (N Y). 2022 Mar 14;8(1):e12258. doi: 10.1002/trc2.12258. eCollection 2022. PMID 35310526
• Hernandez GD, Solinsky CM, Mack WJ, Kono N, Rodgers KE, Wu CY, Mollo AR, Lopez CM, Pawluczyk S, Bauer G, Matthews D, Shi Y, Law M, Rogawski MA, Schneider LS, Brinton RD. Safety, tolerability, and pharmacokinetics of allopregnanolone as a regenerative therapeutic for Alzheimer's disease: A single and multiple ascending dose phase 1b/2a clinical trial. Alzheimers Dement (N Y). 2020 Dec 16;6(1):e12107. doi: 10.1002/trc2.12107. eCollection 2020. PMID 33344752
• Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nat Rev Endocrinol. 2013 Apr;9(4):241-50. doi: 10.1038/nrendo.2013.31. Epub 2013 Feb 26. PMID 23438839
• Brinton RD, Wang JM. Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's disease: allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res. 2006 Jul;3(3):185-90. doi: 10.2174/156720506777632817. PMID 16842093

• Roberta D Brinton, PhD, Principal investigator, University of Arizona
• Lon Schneider, MD, Principal investigator, University of Southern California
• Gerson D Hernandez, MD, MPH, Study director, University of Arizona

NIH grants: R01AG063826