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

Trial Summary

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}

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.

Research Team

Roberta D Brinton, PhD

Principal Investigator

University of Arizona

Lon Schneider, MD

Principal Investigator

University of Southern California

Gerson D Hernandez, MD, MPH

Principal Investigator

University of Arizona

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.

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
• 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.

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

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+

Findings from Research

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 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 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]

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]

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]

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]

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 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]

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]

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]

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]

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

High-dose estradiol improves cognition for women with AD: results of a randomized study. [2022]

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]

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

Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders. [2021]

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]

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

Allopregnanolone impairs episodic memory in healthy women. [2021]