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

• ClinicalTrials.gov Identifier: NCT04838301
• Recruitment Status: Not yet recruiting
• First Posted: April 9, 2021
• Last Update Posted: September 28, 2021
• Sponsor: University of Arizona
• Collaborators: National Institute on Aging (NIA); Syneos Health; ADM Diagnostics, Inc.; University of Southern California
• Information provided by (Responsible Party): Roberta Brinton, University of Arizona

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Dementia; Late Onset Alzheimer Disease; Neurodegenerative Diseases	Drug: Allopregnanolone; Other: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes 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.
• Primary Purpose: Treatment
• 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
• Estimated Study Start Date: November 2021
• Estimated Primary Completion Date: January 2024
• Estimated Study Completion Date: June 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Allo group; Allopregnanolone 4mg IV 30-minute infusion once per week for 12 months.	Drug: Allopregnanolone; Allopregnanolone 4mg IV via 30-minute infusion, once per week.; Other Name: Allo
Placebo Comparator: Control group; Placebo (normal saline) IV 30-minute infusion once per week for 12 months.	Other: Placebo; Normal saline solution IV via 30-minute infusion, once per week

Outcome Measures

Primary Outcome Measures :

1. Hippocampal volume [ Time Frame: Baseline to 12 months ]
   mm3

Secondary Outcome Measures :

1. 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.
2. Cambridge Neuropsychological Test Automated Battery (CANTAB) [ Time Frame: Baseline to 12 months ]
   Composite score (higher score indicate better outcome)
3. 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.
4. 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
5. Safety and tolerability [ Time Frame: Baseline to 12 months ]
   Frequency of adverse events and serious adverse events

Other Outcome Measures:

1. Other regional brain volumes [ Time Frame: Baseline to 12 and 18 months ]
   Change in regional brain volumes (mm3)
2. Diffusion tensor imaging (DTI) [ Time Frame: Baseline to 12 and 18 months ]
   Change in white matter tract diffusion (scalar values and/or mm2/sec)
3. Resting state functional MRI [ Time Frame: Baseline to 12 and 18 months ]
   Change in functional connectivity (z transformed correlations)
4. Arterial spin labeling (ASL) [ Time Frame: Baseline to 12 and 18 months ]
   Change in regional cerebral blood flow (mL/100g)
5. Exploratory blood based biomarkers [ Time Frame: Baseline to 12 and 18 months ]
   Change from baseline in biomarkers of AD pathology, neurogenesis and inflammation
6. Clinical Dementia Rating (CDR) [ Time Frame: Baseline to 12 and 18 months ]
   Sum of boxes score (CDR-SB): range 0-18
7. Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 14 [ Time Frame: Baseline to 12 and 18 months ]
   Total score (range 0-90)
8. Mini Mental State Examination (MMSE) [ Time Frame: Baseline to 12 and 18 months ]
   Total score (range 0-30)
9. Neuropsychiatric Inventory-Questionnaire (NPI-Q) [ Time Frame: Baseline to 12 and 18 months ]
   Total score (range 0-36). Higher scores indicate greater symptom severity
10. EuroQol 5-Dimension / 5-Level health-related quality of life scale scores (EQ-5D-5L) [ Time Frame: Baseline to 12 and 18 months ]
    Reported as frequency, percentage and index value.
11. Quality of Life in Alzheimer's Disease scale (QoL-AD) [ Time Frame: Baseline to 12 and 18 months ]
    Total score (range 13-52). Higher score indicate better QoL
12. Zarit Burden Interview (ZBI) [ Time Frame: Baseline to 12 and 18 months ]
    Total score (range 0-48). Higher scores indicate high burden

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

No Contacts or Locations Provided

More Information

Publications:

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. Review.

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. Review.

• Responsible Party: Roberta Brinton, Director, Center for Innovation in Brain Science; Professor, Departments of Pharmacology and Neurology, University of Arizona
• ClinicalTrials.gov Identifier: NCT04838301
• Other Study ID Numbers: Allo-20-001; R01AG063826 ( U.S. NIH Grant/Contract )
• First Posted: April 9, 2021
• Last Update Posted: September 28, 2021
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Roberta Brinton, University of Arizona:

Mild Alzheimer Disease; Regenerative Therapeutic; APOE ε4; Neurogenesis; Allopregnanolone

Additional relevant MeSH terms:

Alzheimer Disease; Neurodegenerative Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurocognitive Disorders; Mental Disorders; Pregnanolone; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs