Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: April 2025

Detailed Description

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.

Interventions

  • Drug: Allopregnanolone
    • Allopregnanolone 4mg IV via 30-minute infusion, once per week.
  • Other: Placebo
    • Normal saline solution IV via 30-minute infusion, once per week

Arms, Groups and Cohorts

  • Experimental: Allo group
    • Allopregnanolone 4mg IV 30-minute infusion once per week for 12 months.
  • Placebo Comparator: Control group
    • Placebo (normal saline) IV 30-minute infusion once per week for 12 months.

Clinical Trial Outcome Measures

Primary Measures

  • Hippocampal volume
    • Time Frame: Baseline to 12 months
    • mm3

Secondary Measures

  • Cambridge Cognition’s Paired Associates Learning Test
    • Time Frame: Baseline to 12 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)
    • Time Frame: Baseline to 12 months
    • Composite score (higher score indicate better outcome)
  • Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11
    • Time Frame: Baseline to 12 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)
    • Time Frame: Baseline to 12 months
    • iADL subscore (range 0-56): Lower score indicates greater severity
  • Safety and tolerability
    • Time Frame: Baseline to 12 months
    • Frequency of adverse events and serious adverse events

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 55 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Arizona
  • Collaborator
    • National Institute on Aging (NIA)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Roberta Brinton, Director, Center for Innovation in Brain Science; Professor, Departments of Pharmacology and Neurology – University of Arizona
  • Overall Official(s)
    • 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
  • Overall Contact(s)
    • Claudia M Lopez, BS, 520-626-6276, claudiml@arizona.edu

References

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.

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.

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.

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