Allopregnanolone for Alzheimer's Disease

(REGEN-BRAIN© Trial)

Recruiting in Palo Alto (17 mi)

+9 other locations

Overseen by Roberta D Brinton, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Arizona

Must not be taking: Benzodiazepines, Anticonvulsants, Antipsychotics, others

Disqualifiers: Stroke, Seizure disorder, Malignant disease, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop using benzodiazepines, anticonvulsants, antipsychotics, or other drugs that might interact with the GABA-A receptor complex.

What data supports the effectiveness of the drug Allopregnanolone for Alzheimer's Disease?

Research shows that Allopregnanolone, a natural brain steroid, is lower in people with Alzheimer's and has protective effects on brain cells. It has been shown to promote brain cell growth and improve brain function in animal studies, suggesting it might help in Alzheimer's treatment. ^{1 2 3 4 5}

Is allopregnanolone safe for humans?

Allopregnanolone has been tested in early clinical trials for Alzheimer's disease and has shown a high safety profile at sub-sedative doses. Preclinical studies in animals also suggest it is safe and tolerable, with no significant adverse effects observed at therapeutic doses. ^{1 2 5 6 7}

How is the drug allopregnanolone unique for treating Alzheimer's disease?

Allopregnanolone is unique because it is a neurosteroid that promotes brain cell regeneration and repair, which is different from most Alzheimer's treatments that primarily focus on symptom management. It is administered in various ways, including intravenously, and has shown potential to restore cognitive function by enhancing neurogenesis (growth of new brain cells) and oligogenesis (formation of myelin-producing cells). ^{1 2 5 7 8}

Eligibility Criteria

This trial is for men and postmenopausal women aged 55-80 with mild Alzheimer's, as indicated by certain criteria and test scores. Participants must not have had a stroke or other forms of dementia, be free from serious heart, kidney or liver issues, and cannot take specific medications that affect the brain's GABA receptors.

Inclusion Criteria

I am a man or a woman who has gone through menopause.

No medical contraindications to participation

I have the APOE ε4 gene.

Exclusion Criteria

I have had a stroke and my condition is considered moderate to severe.

I do not have serious heart, kidney, or liver problems.

I have had cancer or a recurrence of cancer in the last 5 years.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 4 mg Allopregnanolone or placebo intravenously once per week for 12 months

12 months

Weekly visits (in-person)

Open-label extension

Participants initially in the placebo group receive Allopregnanolone for 6 months

6 months

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• Allopregnanolone (Neurosteroid)
• Placebo (Other)

Trial Overview The study tests Allopregnanolone against a placebo to see if it can help regenerate brain function in Alzheimer's patients. It's a phase 2 trial where participants are randomly assigned to receive either the drug or an inactive substance without knowing which one they're getting.

Participant Groups

Group I: Allo group Experimental Treatment 1 Intervention

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

Group II: Control group Placebo Group 1 Intervention

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

Allopregnanolone is already approved in United States for the following indications:

🇺🇸 Approved in United States as Zulresso for:

• Postpartum depression

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

ATP Clinical Research Costa Mesa, CA

Syrentis Clinical Research Santa Ana, CA

Perseverance Research Center Scottsdale, AZ

Wake Research Los Alamitos, CA

More Trial Locations

Who Is Running the Clinical Trial?

University of Arizona Lead Sponsor

University of Southern California Collaborator

ADM Diagnostics Collaborator

National Institute on Aging (NIA) Collaborator

Syneos Health Collaborator

ADM Diagnostics, Inc. Collaborator

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects. [2021] The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers. Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects). Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n=40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r=-0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04). In summary, our findings indicate that neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. In addition, the APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.

2. United States pubmed.ncbi.nlm.nih.gov

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. [2022] Allopregnanolone is an endogenous neurosteroid with the potential to be a novel regenerative therapeutic for Alzheimer's disease (AD). Foundations of mechanistic understanding and well-established preclinical safety efficacy make it a viable candidate.

3. England pubmed.ncbi.nlm.nih.gov

Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone. [2017] To elucidate the effects of low-dose 17beta-estradiol and norethisterone (hormone therapy [HT]) versus placebo in women with Alzheimer Disease (AD) on cognition, depressive symptoms, and activities of daily living.

4. United States pubmed.ncbi.nlm.nih.gov

High-dose estradiol improves cognition for women with AD: results of a randomized study. [2022] To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD.

5. United States pubmed.ncbi.nlm.nih.gov

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. [2023] Allopregnanolone (ALLO), an endogenous neurosteroid, promoted neurogenesis and oligogenesis and restored cognitive function in animal models of Alzheimer's disease (AD). Based on these discovery research findings, we conducted a randomized-controlled phase 1b/2a multiple ascending dose trial of ALLO in persons with early AD (NCT02221622) to assess safety, tolerability, and pharmacokinetics. Exploratory imaging outcomes to determine whether ALLO impacted hippocampal structure, white matter integrity, and functional connectivity are reported.

6. Switzerland pubmed.ncbi.nlm.nih.gov

Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. [2021] Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer's pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer's mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer's, Parkinson's, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer's disease (AD) that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.

7. United States pubmed.ncbi.nlm.nih.gov

Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. [2020] To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer's disease. These findings have translational relevance to multiple neurodegenerative conditions.

8. Germany pubmed.ncbi.nlm.nih.gov

Allopregnanolone impairs episodic memory in healthy women. [2021] Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the gamma-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women.