Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease

Neurodegenerative Diseases Clinical Trial

— REGEN-BRAIN©  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04838301
• Other study ID #: Allo-20-001
• Secondary ID: R01AG063826
• Status: Recruiting
• Phase: Phase 2
• Start date: August 15, 2023
• Est. completion date: December 2026

Study information

• Verified date: August 2023
• Source: University of Arizona
• Contact: Claudia M Lopez, BS
• Phone: 520-626-6276
• Email: claudiml[@]arizona.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: December 2026
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 55 Years to 80 Years

Eligibility

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 e4 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.

Related Conditions & MeSH terms

• Alzheimer Dementia
• Alzheimer Disease
• Late Onset Alzheimer Disease
• Neurodegenerative Diseases

Intervention

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

Locations

Country	Name	City	State
United States	Optimus U Corporation	Miami	Florida

Sponsors (5)

Lead Sponsor	Collaborator
University of Arizona	ADM Diagnostics, Inc., National Institute on Aging (NIA), Syneos Health, University of Southern California

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Other regional brain volumes	Change in regional brain volumes (mm3)	Baseline to 12 and 18 months
Other	Diffusion tensor imaging (DTI)	Change in white matter tract diffusion (scalar values and/or mm2/sec)	Baseline to 12 and 18 months
Other	Resting state functional MRI	Change in functional connectivity (z transformed correlations)	Baseline to 12 and 18 months
Other	Arterial spin labeling (ASL)	Change in regional cerebral blood flow (mL/100g)	Baseline to 12 and 18 months
Other	Exploratory blood based biomarkers	Change from baseline in biomarkers of AD pathology, neurogenesis and inflammation	Baseline to 12 and 18 months
Other	Clinical Dementia Rating (CDR)	Sum of boxes score (CDR-SB): range 0-18	Baseline to 12 and 18 months
Other	Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 14	Total score (range 0-90)	Baseline to 12 and 18 months
Other	Mini Mental State Examination (MMSE)	Total score (range 0-30)	Baseline to 12 and 18 months
Other	Neuropsychiatric Inventory-Questionnaire (NPI-Q)	Total score (range 0-36). Higher scores indicate greater symptom severity	Baseline to 12 and 18 months
Other	EuroQol 5-Dimension / 5-Level health-related quality of life scale scores (EQ-5D-5L)	Reported as frequency, percentage and index value.	Baseline to 12 and 18 months
Other	Quality of Life in Alzheimer's Disease scale (QoL-AD)	Total score (range 13-52). Higher score indicate better QoL	Baseline to 12 and 18 months
Other	Zarit Burden Interview (ZBI)	Total score (range 0-48). Higher scores indicate high burden	Baseline to 12 and 18 months
Primary	Hippocampal volume	mm3	Baseline to 12 months
Secondary	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
Secondary	Cambridge Neuropsychological Test Automated Battery (CANTAB)	Composite score (higher score indicate better outcome)	Baseline to 12 months
Secondary	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
Secondary	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
Secondary	Safety and tolerability	Frequency of adverse events and serious adverse events	Baseline to 12 months