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

Phase 1

Completed

• Conditions: Mild Cognitive Impairment; Alzheimer Disease
• Interventions: Drug: Allopregnanolone injection (intravenous solution); Drug: Placebo injection (intravenous solution)

• Registration Number: NCT02221622
• Lead Sponsor: University of Southern California

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2014-07-02
• Study Start: 2014-08
• Study First Submitted QC: 2014-08-18
• Study First Posted: 2014-08-20
• Primary Completion: 2018-02
• Study Completion: 2018-02
• Status Verified: 2018-05
• Last Update Submitted: 2019-07-02
• Last Update Posted: 2019-07-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Allopregnanolone 4 mg	Allopregnanolone injection (intravenous solution)	Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
Allopregnanolone 2 mg	Allopregnanolone injection (intravenous solution)	Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
Allopregnanolone 6-18 mg	Allopregnanolone injection (intravenous solution)	Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
Placebo	Placebo injection (intravenous solution)	Drug: Placebo injection (intravenous solution) once per week for 12 weeks

Primary Outcome Measures

Name	Time	Method
Safety profile: ARIA	From Baseline to week 13	MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA
Safety profile: Physical and neurological examination	From Baseline to week 16	To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.
Tolerability - Maximum tolerated dose (MTD)	From Baseline to week 12	Onset of sedation will define the upper most limit of drug dose
Safety profile: Adverse events	From Baseline to week 16	Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.
Safety profile: Clinical laboratory measurements	From Baseline to week 13	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

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC)	Weeks: 1 and 12	Pharmacokinetic parameter.
Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax)	Weeks: 1 and 12	Measurement of maximum concentration
Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax)	Weeks: 1 and 12	Time to attain maximum concentration.
Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL)	Weeks: 1 and 12	Pharmacokinetic parameter.
Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss)	Weeks: 1 and 12	Pharmacokinetic parameter.
Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState)	Baseline to Week 13	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	Baseline and Week 13	Gray matter, white matter and hippocampal volume measurements, including subfield analysis.

Trial Locations

Locations (1)

University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II; 🇺🇸 Los Angeles, California, United States