Clinical trial NCT04838301: Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease
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
Overall status: RECRUITING
Phase: PHASE2
Conditions: Alzheimer Dementia
Late Onset Alzheimer Disease
Neurodegenerative Diseases
Keywords: Mild Alzheimer Disease
Regenerative Therapeutic
APOE ε4
Neurogenesis
Allopregnanolone
Lead sponsor: University of Arizona
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Syneos Health
name: University of Southern California
name: ADM Diagnostics
First posted: 2021-04-09
Enrollment: 200
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Hippocampal volume
timeFrame: Baseline to 12 months
Secondary outcomes:
measure: Cambridge Cognition's Paired Associates Learning Test
timeFrame: Baseline to 12 months
measure: Cambridge Neuropsychological Test Automated Battery (CANTAB)
timeFrame: Baseline to 12 months
measure: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11
timeFrame: Baseline to 12 months
measure: Alzheimer's Disease Cooperative Study (ADCS) Instrumental Activities of Daily (iADL) Living (iADL)
timeFrame: Baseline to 12 months
measure: Safety and tolerability
timeFrame: Baseline to 12 months
Other outcomes:
measure: Other regional brain volumes
timeFrame: Baseline to 12 and 18 months
measure: Diffusion tensor imaging (DTI)
timeFrame: Baseline to 12 and 18 months
measure: Resting state functional MRI
timeFrame: Baseline to 12 and 18 months
measure: Arterial spin labeling (ASL)
timeFrame: Baseline to 12 and 18 months
measure: Exploratory blood based biomarkers
timeFrame: Baseline to 12 and 18 months
measure: Clinical Dementia Rating (CDR)
timeFrame: Baseline to 12 and 18 months
measure: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 14
timeFrame: Baseline to 12 and 18 months
measure: Mini Mental State Examination (MMSE)
timeFrame: Baseline to 12 and 18 months
measure: Neuropsychiatric Inventory-Questionnaire (NPI-Q)
timeFrame: Baseline to 12 and 18 months
measure: EuroQol 5-Dimension / 5-Level health-related quality of life scale scores (EQ-5D-5L)
timeFrame: Baseline to 12 and 18 months
measure: Quality of Life in Alzheimer's Disease scale (QoL-AD)
timeFrame: Baseline to 12 and 18 months
measure: Zarit Burden Interview (ZBI)
timeFrame: Baseline to 12 and 18 months
Locations:
city: Scottsdale
country: United States
facility: Perseverance Research Center
state: Arizona
city: Costa Mesa
country: United States
facility: ATP Clinical Research
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Miami
country: United States
facility: Optimus U Corporation
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health
state: Florida
city: Orlando
country: United States
facility: Combined Research
state: Florida
city: Winter Park
country: United States
facility: Conquest Research
state: Florida
city: Waltham
country: United States
facility: MedVadis Research
state: Massachusetts
Study officials:
affiliation: University of Arizona
name: Roberta D Brinton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Lon Schneider, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Arizona
name: Gerson D Hernandez, MD, MPH
role: STUDY_DIRECTOR
References:
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.
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.
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.
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.