Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: Intramuscular Study (Allo-IM)

Allopregnanolone Regenerative Therapeutic for Early Alzheimer's Disease: IV to IM Bridging Study

The purpose of this study is to identifying the intramuscular dose equivalent to the 4mg intravenous dose and assess its safety and tolerability as a weekly injection.

Study Overview

• Status: Active, not recruiting
• Conditions: Alzheimer Dementia
• Intervention / Treatment: Drug: Allopregnanolone

Detailed Description

The purpose of this bridging study is to advance the therapeutic development of Allopregnanolone (Allo) by using the intramuscular (IM) route of administration as an alternative to the intravenous (IV) route. In order to identify the equivalent IM dose we will conduct pharmacokinetic (PK) analysis previously informed by simulations and modeling. We will recruit a total of 12 participants, both males and females equally distributed, into this single-arm, open-label study.

PK analysis and dose finding will take place for the initial 4 weeks; some participants may not require all 4 weeks of initial dosing to establish maintenance dose. Once maintenance dose is established all participants will receive weekly administration of Allo IM until they complete 12 weeks total of Allo exposure (5 or 6 clinic visits and 6 or 7 home-nurse visits).

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Men or postmenopausal women, aged 55 years or older
• Diagnosis of MCI due to AD or mild AD
• In good general health as evidenced by medical history and with no medical contraindications to participation
• MMSE > 20 at screen
• Caregiver willing and capable to accompany the patient to clinic visits

Exclusion Criteria:

• Daily use of benzodiazepines, sedative/hypnotics, anticonvulsants, antipsychotics, and other drugs that might interact with the GABA-A receptor complex.
• Seizure disorder, history of stroke, focal brain lesion, traumatic brain injury, substance abuse, malignancy.
• Clinically significant laboratory or ECG abnormality obtained at screening visit.
• MRI indicative of significant abnormality, including but not limited to evidence of a single prior hemorrhage or infarct >1 cm3, multiple lacunar infarcts (>1) or evidence of a single prior infarct >1cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions (e.g. abscess or tumor).
• Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI.
• Is currently enrolled in a clinical trial involving an off-label use of an investigational drug or device, or concurrently enrolled in any other type of medical research or observational study judged not to be scientifically or medically compatible with this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Allo IM cohort; Allopregnanolone 4-18mg IM, weekly, for 12 weeks.	Drug: Allopregnanolone; Administration of weekly IM injections of Allopregnanolone.; Other Names: Allo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Adverse events	Incidence and severity of treatment emergent adverse events assessed weekly.	From baseline to visit 16 (14 weeks)
Safety - clinical laboratory measures	Proportion of subjects exceeding pre-established critical laboratory values.	From Baseline to visit 16 (14 weeks)
Safety - clinical assessment	Proportion of subjects with abnormal findings in physical/neurological exams, vital signs and electrocardiograms.	From Baseline to visit 16 (14 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic parameter - Cmax	Determine maximum serum concentration of Allo after IM administration of each dose.	Visits 3 - 6 (up to 4 weeks)
Pharmacokinetic parameter - AUC	Determine the area under the curve after each IM administration of Allo.	Visits 3 - 6 (up to 4 weeks)
Pharmacokinetic parameter - Tmax	Determine the time at which Cmax is attained.	Visits 3 - 6 (up to 4 weeks)
Pharmacokinetic parameter - Clearance	Pharmacokinetic measurement of the volume of plasma from which Allo is completely removed per unit time.	Visits 3 - 6 (up to 4 weeks)
Pharmacokinetic parameter - Volume of distribution	Determine the volume of distribution at steady state of Allo.	Visits 3 - 6 (up to 4 weeks)
Satisfaction and feasibility of home nurse survey	Standardized patient satisfaction questionnaire to assess the feasibility of home-health care visits to administer the study medication and its desirability by participants and caregivers. Levels of satisfaction measured on a 5-point scale (1 = lowest satisfaction, 5 = greatest).	Visits 8-9 and 11-15 (up to 8 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI brain volumes	To evaluate MRI-based brain volumes 1-week before before and 1-week after the administration of Allo IM for 12 weeks (total assessment period of 14 weeks).	Baseline to visit 16 (14 weeks)
Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning (PAL)	Test to evaluate changes in cognition	Baseline to visit 16 (14 weeks)
Mini-Mental State Exam (MMSE)	Test to evaluate changes in cognition.	Baseline to visit 16 (14 weeks)
Alzheimer's Disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog14)	Well known test to evaluate changes in cognition. Scores on this 14 item test range from 0 (best) to 85 (worse); a positive change indicates cognitive worsening.	Baseline to visit 16 (14 weeks)
Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)	Clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively).	Baseline to visit 16 (14 weeks)
Cogstate Alzheimer's battery	Test to evaluate changes in cognition.	Baseline to visit 16 (14 weeks)
Activities of daily living	To assess activities of daily living per the Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-iADLS). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. Scores range from 0-56.	Baseline to visit 16 (14 weeks)
Caregiver burden survey	Assessed per Zarit's burden 22-item questionnaire. Burden measured on a 5-point scale (0 = never burdened, 4 = nearly always burdened). Max score = 88	Baseline to visit 16 (14 weeks)
Actigraphy sleep assessment - Total sleep time	To assess standard sleep parameters using wearable devices (actigraph wristwatch): Total sleep time reported as time in minutes.	Screen to visit 16 (16 weeks)
Actigraphy sleep assessment - Wake after sleep onset	To assess standard sleep parameters using wearable devices (actigraph wristwatch): Wake after sleep onset (WASO) reported as time in minutes.	Screen to visit 16 (16 weeks)
Actigraphy sleep assessment - Sleep efficiency	To assess standard sleep parameters using wearable devices (actigraph wristwatch): Sleep efficiency reported as percentage.	Screen to visit 16 (16 weeks)
Physical activity	To assess daily activity using wearable devices: FitBit.	Screen to visit 16 (16 weeks)

Collaborators and Investigators

• Sponsor: University of Arizona
• Collaborators: University of Southern California; Alzheimer's Association
• Investigators: Principal Investigator: Roberta D Brinton, PhD, University of Arizona; Principal Investigator: Lon S Schneider, MD, MS, University of Southern California

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Actual): December 1, 2022
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: November 19, 2018
• First Posted (Actual): November 20, 2018

Study Record Updates

• Last Update Posted (Actual): April 25, 2023
• Last Update Submitted That Met QC Criteria: April 22, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Dementia; Mild cognitive impairment; Regenerative therapeutic; Drug development
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Dementia; Alzheimer Disease; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics; Pregnanolone
• Other Study ID Numbers: AlloPhase1-IM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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