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

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ClinicalTrials.gov Identifier: NCT02221622
Recruitment Status : Completed
First Posted : August 20, 2014
Last Update Posted : June 4, 2018
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Roberta Brinton, University of Southern California

Study Description
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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.

Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Alzheimer Disease Drug: Allopregnanolone injection (intravenous solution) Drug: Placebo injection (intravenous solution) Phase 1

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase 1
Study Start Date : August 2014
Actual Primary Completion Date : February 2018
Actual Study Completion Date : February 2018

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Allopregnanolone 2 mg
Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
 Drug: Allopregnanolone injection (intravenous solution)
Allopregnanolone intravenous infusion
Other Names:
  • 3α,5α-tetrahydroprogesterone
  • 3α-hydroxy-5α-pregnan-20-one
Experimental: Allopregnanolone 4 mg
Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
 Drug: Allopregnanolone injection (intravenous solution)
Allopregnanolone intravenous infusion
Other Names:
  • 3α,5α-tetrahydroprogesterone
  • 3α-hydroxy-5α-pregnan-20-one
Experimental: Allopregnanolone 6-18 mg
Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
 Drug: Allopregnanolone injection (intravenous solution)
Allopregnanolone intravenous infusion
Other Names:
  • 3α,5α-tetrahydroprogesterone
  • 3α-hydroxy-5α-pregnan-20-one
Placebo Comparator: Placebo
Drug: Placebo injection (intravenous solution) once per week for 12 weeks
 Drug: Placebo injection (intravenous solution)
Placebo intravenous infusion


Outcome Measures
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Primary Outcome Measures :
  1. Safety profile: Adverse events [ Time Frame: From Baseline to week 16 ]
    Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.

  2. Safety profile: Clinical laboratory measurements [ Time Frame: 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


  3. Safety profile: ARIA [ Time Frame: From Baseline to week 13 ]
    MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA

  4. Safety profile: Physical and neurological examination [ Time Frame: From Baseline to week 16 ]
    To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.

  5. Tolerability - Maximum tolerated dose (MTD) [ Time Frame: From Baseline to week 12 ]
    Onset of sedation will define the upper most limit of drug dose


Secondary Outcome Measures :
  1. Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax) [ Time Frame: Weeks: 1 and 12 ]
    Measurement of maximum concentration

  2. Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax) [ Time Frame: Weeks: 1 and 12 ]
    Time to attain maximum concentration.

  3. Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC) [ Time Frame: Weeks: 1 and 12 ]
    Pharmacokinetic parameter.

  4. Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL) [ Time Frame: Weeks: 1 and 12 ]
    Pharmacokinetic parameter.

  5. Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss) [ Time Frame: Weeks: 1 and 12 ]
    Pharmacokinetic parameter.

  6. Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState) [ Time Frame: 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)

  7. Brain MRI volumetrics [ Time Frame: Baseline and Week 13 ]
    Gray matter, white matter and hippocampal volume measurements, including subfield analysis.


Eligibility Criteria
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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02221622


Locations
United States, California
University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II
Los Angeles, California, United States, 90033
Sponsors and Collaborators
University of Southern California
National Institute on Aging (NIA)
Investigators
Principal Investigator: Roberta D Brinton, Ph.D. University of Southern California
Principal Investigator: Lon S Schneider, M.D. University of Southern California
More Information
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Responsible Party: Roberta Brinton, Professor, University of Southern California
ClinicalTrials.gov Identifier: NCT02221622     History of Changes
Other Study ID Numbers: AlloPhase1
1UF1AG046148 ( U.S. NIH Grant/Contract )
First Posted: August 20, 2014    Key Record Dates
Last Update Posted: June 4, 2018
Last Verified: May 2018

Keywords provided by Roberta Brinton, University of Southern California:
Alzheimer's disease
Mild Cognitive Impairment
Dementia
Regenerative therapeutic

Additional relevant MeSH terms:
Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
 Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Pharmaceutical Solutions
Pregnanolone
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs