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Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD (Allo)

Primary Purpose

Mild Cognitive Impairment, Alzheimer Disease

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Allopregnanolone injection (intravenous solution)
Placebo injection (intravenous solution)
Sponsored by
University of Southern California
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mild Cognitive Impairment focused on measuring Alzheimer's disease, Mild Cognitive Impairment, Dementia, Regenerative therapeutic

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men or postmenopausal women
  • 55 years of age or older
  • Diagnosis of MCI due to AD or mild AD
  • MMSE > 20 at screen
  • Capacity to provide informed consent
  • Residing in the community with a caregiver able to accompany the patient to clinic visits
  • No medical contraindications to participation
  • Willingness to comply with study procedures

Exclusion Criteria:

  • 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
  • MRI indicative of any other significant abnormality, including but not limited to evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions
  • Any condition that would contraindicate an MRI such as the presence of metallic objects in the eyes, skin, heart, or body

Sites / Locations

  • University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Allopregnanolone 2 mg

Allopregnanolone 4 mg

Allopregnanolone 6-18 mg

Placebo

Arm Description

Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks

Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks

Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks

Drug: Placebo injection (intravenous solution) once per week for 12 weeks

Outcomes

Primary Outcome Measures

Safety profile: Adverse events
Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.
Safety profile: Clinical laboratory measurements
Evaluating the proportion of subjects exceeding pre-established critical values per treatment arm: Alanine aminotransferase (ALT, U/L) > 5 times upper normal limit Aspartate aminotransferase (AST, U/L) > 5 times upper normal limit Total serum bilirubin (mg/dl) > 2 times upper normal limit Serum creatinine (mg/dl) > 2 times upper normal limit Serum creatine phosphokinase (U/L) > 5 times upper normal limit
Safety profile: ARIA
MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA
Safety profile: Physical and neurological examination
To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.
Tolerability - Maximum tolerated dose (MTD)
Onset of sedation will define the upper most limit of drug dose

Secondary Outcome Measures

Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax)
Measurement of maximum concentration
Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax)
Time to attain maximum concentration.
Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC)
Pharmacokinetic parameter.
Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL)
Pharmacokinetic parameter.
Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss)
Pharmacokinetic parameter.
Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState)
Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState)
Brain MRI volumetrics
Gray matter, white matter and hippocampal volume measurements, including subfield analysis.

Full Information

First Posted
July 2, 2014
Last Updated
July 2, 2019
Sponsor
University of Southern California
Collaborators
National Institute on Aging (NIA)
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1. Study Identification

Unique Protocol Identification Number
NCT02221622
Brief Title
Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD
Acronym
Allo
Official Title
Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase 1
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
August 2014 (undefined)
Primary Completion Date
February 2018 (Actual)
Study Completion Date
February 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Southern California
Collaborators
National Institute on Aging (NIA)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and tolerability of allopregnanolone, a naturally occurring brain steroid, in mild cognitive impairment and early Alzheimer's disease participants. The primary goal is to determine the maximally tolerated dose.
Detailed Description
1) Each dose group will be comprised of 8 participants (6 randomized to allopregnanolone; 2 randomized to placebo) administered one dose of allopregnanolone or placebo once per week for 12 weeks. A higher dose will be administered to the next group of participants when the lower dose is shown to be safe and tolerable. 2) Pharmacokinetic analyses will be conducted on blood samples taken from participants at the beginning and end of the trial. 3) The trial will assess safety including via MRI brain imaging.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mild Cognitive Impairment, Alzheimer Disease
Keywords
Alzheimer's disease, Mild Cognitive Impairment, Dementia, Regenerative therapeutic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Allopregnanolone 2 mg
Arm Type
Experimental
Arm Description
Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
Arm Title
Allopregnanolone 4 mg
Arm Type
Experimental
Arm Description
Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
Arm Title
Allopregnanolone 6-18 mg
Arm Type
Experimental
Arm Description
Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Drug: Placebo injection (intravenous solution) once per week for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Allopregnanolone injection (intravenous solution)
Other Intervention Name(s)
3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one
Intervention Description
Allopregnanolone intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Placebo injection (intravenous solution)
Intervention Description
Placebo intravenous infusion
Primary Outcome Measure Information:
Title
Safety profile: Adverse events
Description
Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.
Time Frame
From Baseline to week 16
Title
Safety profile: Clinical laboratory measurements
Description
Evaluating the proportion of subjects exceeding pre-established critical values per treatment arm: Alanine aminotransferase (ALT, U/L) > 5 times upper normal limit Aspartate aminotransferase (AST, U/L) > 5 times upper normal limit Total serum bilirubin (mg/dl) > 2 times upper normal limit Serum creatinine (mg/dl) > 2 times upper normal limit Serum creatine phosphokinase (U/L) > 5 times upper normal limit
Time Frame
From Baseline to week 13
Title
Safety profile: ARIA
Description
MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA
Time Frame
From Baseline to week 13
Title
Safety profile: Physical and neurological examination
Description
To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.
Time Frame
From Baseline to week 16
Title
Tolerability - Maximum tolerated dose (MTD)
Description
Onset of sedation will define the upper most limit of drug dose
Time Frame
From Baseline to week 12
Secondary Outcome Measure Information:
Title
Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax)
Description
Measurement of maximum concentration
Time Frame
Weeks: 1 and 12
Title
Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax)
Description
Time to attain maximum concentration.
Time Frame
Weeks: 1 and 12
Title
Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC)
Description
Pharmacokinetic parameter.
Time Frame
Weeks: 1 and 12
Title
Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL)
Description
Pharmacokinetic parameter.
Time Frame
Weeks: 1 and 12
Title
Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss)
Description
Pharmacokinetic parameter.
Time Frame
Weeks: 1 and 12
Title
Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState)
Description
Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState)
Time Frame
Baseline to Week 13
Title
Brain MRI volumetrics
Description
Gray matter, white matter and hippocampal volume measurements, including subfield analysis.
Time Frame
Baseline and Week 13

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men or postmenopausal women 55 years of age or older Diagnosis of MCI due to AD or mild AD MMSE > 20 at screen Capacity to provide informed consent Residing in the community with a caregiver able to accompany the patient to clinic visits No medical contraindications to participation Willingness to comply with study procedures Exclusion Criteria: 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 MRI indicative of any other significant abnormality, including but not limited to evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space occupying lesions Any condition that would contraindicate an MRI such as the presence of metallic objects in the eyes, skin, heart, or body
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roberta D Brinton, Ph.D.
Organizational Affiliation
University of Southern California
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lon S Schneider, M.D.
Organizational Affiliation
University of Southern California
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33344752
Citation
Hernandez GD, Solinsky CM, Mack WJ, Kono N, Rodgers KE, Wu CY, Mollo AR, Lopez CM, Pawluczyk S, Bauer G, Matthews D, Shi Y, Law M, Rogawski MA, Schneider LS, Brinton RD. 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. Alzheimers Dement (N Y). 2020 Dec 16;6(1):e12107. doi: 10.1002/trc2.12107. eCollection 2020.
Results Reference
derived

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Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD

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