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Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease (REGEN-BRAIN©)

Primary Purpose

Alzheimer Dementia, Late Onset Alzheimer Disease, Neurodegenerative Diseases

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Allopregnanolone
Placebo
Sponsored by
University of Arizona
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alzheimer Dementia focused on measuring Mild Alzheimer Disease, Regenerative Therapeutic, APOE ε4, Neurogenesis, Allopregnanolone

Eligibility Criteria

55 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Optimus U CorporationRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Allo group

Control group

Arm Description

Allopregnanolone 4mg IV 30-minute infusion once per week for 12 months.

Placebo (normal saline) IV 30-minute infusion once per week for 12 months.

Outcomes

Primary Outcome Measures

Hippocampal volume
mm3

Secondary Outcome Measures

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.
Cambridge Neuropsychological Test Automated Battery (CANTAB)
Composite score (higher score indicate better outcome)
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11
Total score (range 0 to 70); higher scores indicate poor performance.
Alzheimer's Disease Cooperative Study (ADCS) Instrumental Activities of Daily (iADL) Living (iADL)
iADL subscore (range 0-56): Lower score indicates greater severity
Safety and tolerability
Frequency of adverse events and serious adverse events

Full Information

First Posted
March 25, 2021
Last Updated
August 30, 2023
Sponsor
University of Arizona
Collaborators
National Institute on Aging (NIA), Syneos Health, ADM Diagnostics, Inc., University of Southern California
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1. Study Identification

Unique Protocol Identification Number
NCT04838301
Brief Title
Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 15, 2023 (Actual)
Primary Completion Date
April 2025 (Anticipated)
Study Completion Date
December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Arizona
Collaborators
National Institute on Aging (NIA), Syneos Health, ADM Diagnostics, Inc., University of Southern California

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alzheimer Dementia, Late Onset Alzheimer Disease, Neurodegenerative Diseases
Keywords
Mild Alzheimer Disease, Regenerative Therapeutic, APOE ε4, Neurogenesis, Allopregnanolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
After 12 months participants and study personnel will be aware of the open label phase, but initial randomization will remain blind during the entire length of the study (placebo-controlled and open-label periods); that is, all participants and study personnel are blinded to each participant's randomization to initial treatment group.
Allocation
Randomized
Enrollment
200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Allo group
Arm Type
Experimental
Arm Description
Allopregnanolone 4mg IV 30-minute infusion once per week for 12 months.
Arm Title
Control group
Arm Type
Placebo Comparator
Arm Description
Placebo (normal saline) IV 30-minute infusion once per week for 12 months.
Intervention Type
Drug
Intervention Name(s)
Allopregnanolone
Other Intervention Name(s)
Allo
Intervention Description
Allopregnanolone 4mg IV via 30-minute infusion, once per week.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Normal saline solution IV via 30-minute infusion, once per week
Primary Outcome Measure Information:
Title
Hippocampal volume
Description
mm3
Time Frame
Baseline to 12 months
Secondary Outcome Measure Information:
Title
Cambridge Cognition's Paired Associates Learning Test
Description
Total errors score (adjusted) - number of errors made by the participant (range: 0 to ~120). Higher scores indicate poor performance.
Time Frame
Baseline to 12 months
Title
Cambridge Neuropsychological Test Automated Battery (CANTAB)
Description
Composite score (higher score indicate better outcome)
Time Frame
Baseline to 12 months
Title
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11
Description
Total score (range 0 to 70); higher scores indicate poor performance.
Time Frame
Baseline to 12 months
Title
Alzheimer's Disease Cooperative Study (ADCS) Instrumental Activities of Daily (iADL) Living (iADL)
Description
iADL subscore (range 0-56): Lower score indicates greater severity
Time Frame
Baseline to 12 months
Title
Safety and tolerability
Description
Frequency of adverse events and serious adverse events
Time Frame
Baseline to 12 months
Other Pre-specified Outcome Measures:
Title
Other regional brain volumes
Description
Change in regional brain volumes (mm3)
Time Frame
Baseline to 12 and 18 months
Title
Diffusion tensor imaging (DTI)
Description
Change in white matter tract diffusion (scalar values and/or mm2/sec)
Time Frame
Baseline to 12 and 18 months
Title
Resting state functional MRI
Description
Change in functional connectivity (z transformed correlations)
Time Frame
Baseline to 12 and 18 months
Title
Arterial spin labeling (ASL)
Description
Change in regional cerebral blood flow (mL/100g)
Time Frame
Baseline to 12 and 18 months
Title
Exploratory blood based biomarkers
Description
Change from baseline in biomarkers of AD pathology, neurogenesis and inflammation
Time Frame
Baseline to 12 and 18 months
Title
Clinical Dementia Rating (CDR)
Description
Sum of boxes score (CDR-SB): range 0-18
Time Frame
Baseline to 12 and 18 months
Title
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 14
Description
Total score (range 0-90)
Time Frame
Baseline to 12 and 18 months
Title
Mini Mental State Examination (MMSE)
Description
Total score (range 0-30)
Time Frame
Baseline to 12 and 18 months
Title
Neuropsychiatric Inventory-Questionnaire (NPI-Q)
Description
Total score (range 0-36). Higher scores indicate greater symptom severity
Time Frame
Baseline to 12 and 18 months
Title
EuroQol 5-Dimension / 5-Level health-related quality of life scale scores (EQ-5D-5L)
Description
Reported as frequency, percentage and index value.
Time Frame
Baseline to 12 and 18 months
Title
Quality of Life in Alzheimer's Disease scale (QoL-AD)
Description
Total score (range 13-52). Higher score indicate better QoL
Time Frame
Baseline to 12 and 18 months
Title
Zarit Burden Interview (ZBI)
Description
Total score (range 0-48). Higher scores indicate high burden
Time Frame
Baseline to 12 and 18 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Claudia M Lopez, BS
Phone
520-626-6276
Email
claudiml@arizona.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roberta D Brinton, PhD
Organizational Affiliation
University of Arizona
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lon Schneider, MD
Organizational Affiliation
University of Southern California
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Gerson D Hernandez, MD, MPH
Organizational Affiliation
University of Arizona
Official's Role
Study Director
Facility Information:
Facility Name
Optimus U Corporation
City
Miami
State/Province
Florida
ZIP/Postal Code
33135
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yaneicy Gonazalez Rojas, MD
First Name & Middle Initial & Last Name & Degree
Yaneicy Gonazalez Rojas, MD

12. IPD Sharing Statement

Citations:
PubMed Identifier
33344752
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.
Results Reference
background
PubMed Identifier
23438839
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.
Results Reference
background
PubMed Identifier
16842093
Citation
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.
Results Reference
background
PubMed Identifier
35310526
Citation
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. Erratum In: Alzheimers Dement (N Y). 2022 Jul 26;8(1):e12300.
Results Reference
derived

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Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease

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