Allopregnanolone for Alzheimer's Disease

(REGEN-BRAIN© Trial)

Recruiting at 9 trial locations

Overseen By Claudia M Lopez, BS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Arizona

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

Disqualifiers: Stroke, Seizure disorder, Malignant disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether Allopregnanolone, administered through weekly infusions, can safely improve brain health in people with Alzheimer's disease. Participants will receive either the actual treatment or a placebo (a harmless, inactive substance) to compare results. The trial seeks men and postmenopausal women diagnosed with Alzheimer's who have certain genetic markers and can undergo the treatment process without interfering medications. This trial may suit those living with Alzheimer's who meet these specific criteria. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Allopregnanolone is generally safe for humans. In one study, people with early Alzheimer's disease received Allopregnanolone through an IV for 12 weeks, and it was safe and well-tolerated at all doses. Another study also found that Allopregnanolone was safe and well-tolerated at different doses for people with early Alzheimer's. These results support further testing in clinical trials. Overall, the safety data from these studies are promising for those considering participation in trials with Allopregnanolone. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Most treatments for Alzheimer's disease focus on managing symptoms or slowing disease progression through medications like cholinesterase inhibitors (such as donepezil) and NMDA receptor antagonists (like memantine). However, allopregnanolone stands out because it's a neurosteroid with potential regenerative properties, targeting neural growth and repair. This unique mechanism could offer not just symptom management, but also the possibility of reversing some cognitive decline by promoting brain cell growth. Researchers are excited because allopregnanolone might address the root causes of Alzheimer's, offering hope for more substantial and lasting improvements in brain health.

What evidence suggests that Allopregnanolone might be an effective treatment for Alzheimer's disease?

Research suggests that allopregnanolone could be a promising treatment for Alzheimer's disease. Studies in mice have shown that it can improve memory and promote the growth of new brain cells, which are crucial for thinking and memory. This brain chemical aids in brain repair, potentially reversing some damage caused by Alzheimer's. Although no treatment has been proven to stop Alzheimer's yet, allopregnanolone's ability to assist brain healing makes it a hopeful option. In this trial, participants will receive either allopregnanolone or a placebo to further investigate its potential benefits for people with Alzheimer's. ^{2 4 5 6 7}

Who Is on the Research Team?

Gerson D Hernandez, MD, MPH

Principal Investigator

University of Arizona

Roberta D Brinton, PhD

Principal Investigator

University of Arizona

Lon Schneider, MD

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Allopregnanolone
• Placebo

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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

University of Southern California

Collaborator

Trials

956

Recruited

1,609,000+

ADM Diagnostics

Collaborator

Trials

2

Recruited

300+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Syneos Health

Collaborator

Trials

181

Recruited

69,600+

ADM Diagnostics, Inc.

Collaborator

Trials

1

Recruited

200+

Published Research Related to This Trial

Allopregnanolone was found to be safe and well tolerated in a trial involving 24 participants with early Alzheimer's disease, with no significant adverse events related to the treatment, indicating its potential as a therapeutic option.

The study established a maximum tolerated dose (MTD) for allopregnanolone, with pharmacokinetic data showing a predictable linear dose-response, supporting further investigation into its efficacy for Alzheimer's disease.

NCBI (Pubmed)

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. Hernandez, GD., Solinsky, CM., Mack, WJ., et al.[2022]

In a study of 20 postmenopausal women with Alzheimer's disease, treatment with a high dose of estrogen (0.10 mg/day of 17 beta-estradiol) for 8 weeks significantly improved attention and various memory functions compared to a placebo.

Estrogen treatment also appeared to influence the insulin-like growth factor (IGF) system, reducing levels of IGF binding protein-3, which suggests a complex interaction between estrogen and neuroendocrine markers that may affect cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose estradiol improves cognition for women with AD: results of a randomized study. Asthana, S., Baker, LD., Craft, S., et al.[2022]

Allopregnanolone levels are significantly reduced in the temporal cortex of Alzheimer's disease (AD) patients compared to cognitively intact controls, indicating a potential link between this neurosteroid and the progression of AD.

The study found that patients with the APOE4 allele, a genetic risk factor for AD, also exhibited lower levels of allopregnanolone, suggesting that neurosteroid dysregulation may play a role in the disease's pathophysiology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopregnanolone levels are reduced in temporal cortex in patients with Alzheimer's disease compared to cognitively intact control subjects. Naylor, JC., Kilts, JD., Hulette, CM., et al.[2021]

Allopregnanolone (Allo) has shown promising effects in a mouse model of Alzheimer's disease by promoting neurogenesis and reducing harmful β-amyloid levels, indicating its potential as a regenerative treatment for neurological conditions.

A weekly treatment regimen of Allo at sub-sedative doses was found to be optimal for safety and efficacy, suggesting that careful dosing and administration routes will be crucial for translating its benefits to human patients with chronic neurological disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. Irwin, RW., Solinsky, CM., Brinton, RD.[2021]

In a study involving 28 healthy women, intravenous administration of allopregnanolone was found to significantly impair episodic memory, as evidenced by lower memory scores after the injection compared to before.

No significant effects were observed on semantic memory or working memory tasks, indicating that allopregnanolone specifically affects episodic memory, though individual responses varied widely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopregnanolone impairs episodic memory in healthy women. Kask, K., Bäckström, T., Nilsson, LG., et al.[2021]

In a 12-month study involving 55 women with Alzheimer's Disease, hormone therapy (HT) with low-dose 17beta-estradiol and norethisterone showed a significant reduction in depressive symptoms compared to placebo, particularly in women without the ApoE epsilon4 allele.

While there were no significant differences in cognitive measures overall, women without the ApoE epsilon4 allele experienced improvements in mood and memory, suggesting that HT may be beneficial for certain subgroups of women with Alzheimer's Disease.

NCBI (Pubmed)

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. Valen-Sendstad, A., Engedal, K., Stray-Pedersen, B., et al.[2017]

Allopregnanolone, administered through various routes (subcutaneous, intravenous, etc.), showed promising neurogenic effects in animal models of Alzheimer's disease, significantly increasing markers of neurogenesis in the brain at safe and tolerable doses.

The study established a no observable adverse effect level (NOAEL) of 0.5 mg/kg and a maximally tolerated dose (MTD) of 2 mg/kg in female rats, suggesting a safe dose range for initial clinical trials in humans, with predicted MTD in human females being 0.37 mg/kg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. Irwin, RW., Solinsky, CM., Loya, CM., et al.[2020]

In a phase 1b/2a trial involving 24 participants with early Alzheimer's disease, treatment with allopregnanolone (ALLO) significantly slowed the decline in hippocampal volume and, in some cases, even reversed it, particularly in APOE ε4 carriers.

ALLO treatment also improved white matter integrity and strengthened functional connectivity in brain regions vulnerable to Alzheimer's, suggesting its potential as a regenerative therapy for mild Alzheimer's disease.

NCBI (Pubmed)

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. Raikes, AC., Hernandez, GD., Matthews, DC., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10124616/

Allopregnanolone as regenerative therapeutic for Alzheimer's ... We review a translational development plan to advance allopregnanolone to the clinic as a regenerative therapeutic for neurodegenerative diseases, in ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2851948/

Allopregnanolone reverses neurogenic and cognitive ... In summary, results of the current analysis show that APα reversed deficits in SGZ neurogenesis, learning, and memory in the 3xTgAD mouse model of Alzheimer's ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2352289522000777

Allopregnanolone: Regenerative therapeutic to restore ... 3α, 5α‐tetrahydroprogesterone ... allopregnanolone as a regenerative therapeutic for Alzheimer's disease: structural effects and functional connectivity outcomes.

4. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.12107

Safety, tolerability, and pharmacokinetics of allopregnanolone ... Thus far no interventions have demonstrated meaningful therapeutic efficacy to treat Alzheimer's disease (AD) resulting in a 99.6% clinical ...

5. frontiersin.org frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2014.00203/full

Frontiers in therapeutic development of allopregnanolone ... Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer's disease, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7744018/

A single and multiple ascending dose phase 1b/2a clinical trial Interpretation: Allopregnanolone administered intravenously over 12 weeks in patients with early AD was safe and well tolerated at every dose.

7. alz-journals.onlinelibrary.wiley.com alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/trc2.12107

Safety, tolerability, and pharmacokinetics of allopregnanolone ... Allopregnanolone was well tolerated and safe across all doses in persons with early AD. Safety, MTD, and PK profiles support advancement of ...