Allopregnanolone as a Regenerative Treatment for Parkinson's Disease (Allo-PD)

Allopregnanolone as a Regenerative Treatment for Parkinson's Disease: An Open-label, Pilot Clinical Trial

The goal of this open-label, pilot clinical trial is to test allopregnanolone as a regenerative treatment in patients with Parkinson's disease (PD). The main questions this study aims to answer are:

1. Is a large-scale clinical trial testing how well it works in patients with PD feasible?
2. Is allopregnanolone safe and well-tolerated in patients with PD.
3. Can we see any signals of changes in imaging and clinical scales?

Participants will receive a weekly infusion in their vein of allopregnanolone for a total of 12 weeks. There is no placebo so everyone receives allopregnanolone and "Open-label" means the study is not blinded so both the participant and investigators know the assigned treatment.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Allopregnanolone

Detailed Description

This is an open-label, pilot clinical trial of allopregnanolone (Allo) as a regenerative treatment for Parkinson's disease. A total of 10 study participants will receive weekly infusions of Allo for 12 weeks. Participants will be male and female, age 40-80 years with a history of idiopathic, sporadic PD who have a Hoehn & Yahr stage 1-4. Allo is a potent neuroregenerative agent that promotes proliferation of human neural stem cells and has the potential to function as a regenerative therapeutic to restore motor function in persons with PD. Results from several preclinical studies in rodent models of PD confirm improved motor function after Allo treatment.

Primary Objective: To assess the feasibility of a large-scale trial to determine the efficacy of weekly infusions of Allo in in patients with Idiopathic sporadic PD.

Secondary Objectives: To evaluate the safety and tolerability of weekly infusions of Allo in participants with idiopathic sporadic PD, and assess single-dose pharmacokinetics of allopregnanolone.

Tertiary / Exploratory Objectives: To assess efficacy signals of weekly infusions of Allo in participants with idiopathic sporadic PD.

• Determine target engagement of Allo using dopamine transporter (DaT) imaging and magnetic resonance imaging (MRI).
• Evaluate effect of Allo on motor function tests.
• Evaluate the effect of Allo on cognitive function tests and clinical ratings.
• Compare response to Allo administration between APOE4 carriers and non-carriers.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Claudia M Lopez, BS; Phone Number: 520-626-6276; Email: claudiml@arizona.edu

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85721
      • Recruiting
      • The University of Arizona Clinical & Translational Science Research Center
      • Contact: Dakota Darby; Email: dakotadarby@arizona.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• History of Idiopathic sporadic Parkinson disease
• Hoehn & Yahr stage 1-4
• Have been on stable doses of all anti-Parkinson's medications for 30 days prior to screening
• Provision of signed and dated informed consent form

Exclusion Criteria:

• Evidence of Parkinsonian syndrome.
• Any conditions that would contraindicate MRI studies.
• Undergone deep brain stimulation (DBS) surgery as treatment for PD.
• Iodine allergy, known serious hypersensitivity to ioflupane I-123, or other inability to undergo DaTscan.
• Clinically significant abnormal laboratory value and/or clinically significant unstable medical or psychiatric illness.
• History within the last 5 years of a primary or recurrent malignant disease, with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or prostate cancer in situ with a post-treatment prostatic-specific antigen within normal range.
• Serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other than PD), psychiatric, immunologic, or hematologic disease, and any other conditions that, in the investigator's opinion, could interfere with the safety and efficacy analyses in this study.
• History of chronic alcohol or substance abuse/dependence within the past 3 years.
• Current use of benzodiazepines, anticonvulsants, antipsychotics, or other drugs that might interact with the gamma-aminobutyric acid-A (GABA-A) receptor complex; use of calcium-channel blockers (e.g., amlodipine); use of dietary supplements containing Pregnenolone.
• Treatment with another investigational drug within 3 months of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Allo APOE4 carriers; Group of 5 participants who are carriers of the APOE4 gene and will receive allopregnanolone 4mg administered weekly via a 30-min IV infusion for a duration of 12 weeks.	Drug: Allopregnanolone; Allopregnanolone is a neurosteroid ( 3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) and by-product of the metabolism of the hormone progesterone.
Active Comparator: Allo APOE4 none-carriers; Group of 5 participants who are none-carriers of the APOE4 gene and will receive allopregnanolone 4mg administered weekly via a 30-min IV infusion for a duration of 12 weeks.	Drug: Allopregnanolone; Allopregnanolone is a neurosteroid ( 3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) and by-product of the metabolism of the hormone progesterone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study completion	Proportion of participant progression to study completion.	Week 13

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Proportion of participants with adverse events to assess safety.	Weekly from Baseline to Week 16
Infusion Reactions	Proportion of participants with infusion reactions to assess tolerability.	Weekly from Week 1 to Week 16
Pharmacokinetics: Peak Plasma Concentration (Cmax)	The highest concentration in plasma of allopregnanolone after an IV dose.	Week 1
Pharmacokinetics: Time of peak concentration (tmax)	Time required to achieve peak plasma levels	Week 1
Pharmacokinetics: Half-life (t1/2)	The time required for plasma concentration of Allopregnanolone to decrease by 50%.	Week 1
Pharmacokinetics: Area under the plasma concentration versus time curve (AUC)	The concentration of phytoSERMs in blood plasma as a function of time. Gives insight into the extent of exposure to phytoSERM and its clearance rate from the body.	Week 1

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dopamine transporter (DaT) SPECT imaging	Change from baseline in DaT imaging z-scores.	Baseline to week 13
MRI: Regional brain volumes	T1-weighted volumetric MRI (mm3).	Screening to week 13
MRI: Fractional Anisotropy	Multi-band multi-shell Diffusion Tensor Imaging (DTI) to measure changes in white matter tract integrity.	Screening to week 13
MRI: Quantitative anisotropy	DTI to measure changes in white matter tract integrity. The amount of anisotropic spins that diffuse along the fiber orientation.	Screening to week 13
MRI: Functional connectivity	Resting state functional MRI (rs-fMRI) to measure changes in intrinsic connectivity, which also correlates to neuronal function.	Screening to week 13
Mean rate of change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score part I (non-motor EDL)	MDS-UPDRS part I will evaluate non-motor Experiences of Daily Living (cognition, behavior, mood, etc.).	Baseline to week 13
Mean rate of change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score part II (motor EDL)	MDS-UPDRS part II will evaluate motor Experiences of Daily Living (speech, eating, grooming, walking, etc.). The UPDRS Part II consists of 13 items scored between 0 and 4. The sum score ranges from 0 to 52, higher scores denote greater disability.	Baseline to week 13
Mean rate of change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score part III (motor examination)	MDS-UPDRS part III (motor subscale) assesses the motor signs of PD. It consists of 27 items and sub items scored between 0 and 4. The sum score ranges from 0 to 108, higher scores denote greater disability.	Baseline to week 13
Mean rate of change in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score part IV (motor complications)	MDS-UPDRS part IV of the scale assesses two motor complications, dyskinesias and motor fluctuations that include OFF-state dystonia. Score ranges from 0-44, higher scores denote greater disability. The UPDRS Part III (motor subscale) consists of 27 items and sub items scored between 0 and 4. The sum score ranges from 0 to 108, higher scores denote greater disability.	Baseline to week 13
Mean rate of change in the Unified Dyskinesia Rating Scale (UDysRS) total score	Scale designed to capture the essential features of dyskinesia in PD. Score range is 0-104, higher scores denote greater disability.	Baseline to week 13
Change from baseline in Montreal Cognitive Assessment (MoCA) score	Test used to detect cognitive impairment, measuring executive functions and multiple cognitive domains. Score ranges from 0-30, with higher scores denoting better performance.	Baseline to week 13
Change from baseline in Parkinson's disease Questionnaire (PDQ-39).	PD specific health status questionnaire comprising 39 items. Items are grouped into eight scales that are scored by expressing summed item scores as a percentage score ranging between 0 and 100.	Baseline to week 13
Change from baseline in Hamilton Depression Rating Scale (HAM-D)	Scale used to measure depression severity. Score ranges from 0-52, with higher scores indicating worst outcome.	Baseline to week 13
Cambridge Cognition's Paired Associates Learning (PAL) Test	Total errors score (adjusted) - number of errors made by the participant (range: 0 to ~120). Higher scores indicate poor performance.	Baseline to week 13
Cambridge Cognition's Motor Screening Task (MOT)	Outcome measures cover accuracy and difficulty speed adjustment. The mean latency for a subject to correctly respond to the stimulus on screen during assessed trials, measured in milliseconds. Range from 0 to 6000ms.	Baseline to week 13
Cambridge Cognition's One Touch Stockings of Cambridge (OTS)	It assesses both the spatial planning and the working memory subdomains. Outcome measure is the total number of assessed trials where the subject chose the correct answer on their first attempt. Range 0 to 15.	Baseline to week 13

Collaborators and Investigators

• Sponsor: Roberta Brinton
• Investigators: Study Director: Gerson D Hernandez, MD, MPH, University of Arizona; Principal Investigator: Scott Sherman, MD, University of Arizona; Study Chair: Roberta D Brinton, PhD, University of Arizona

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2024
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: February 8, 2024
• First Submitted That Met QC Criteria: February 8, 2024
• First Posted (Actual): February 16, 2024

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 15, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Parkinson; Allopregnanolone; Regenerative therapeutic
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics; Pregnanolone
• Other Study ID Numbers: CIBS-2023-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No